Deuterated caffeine and uses thereof

ABSTRACT

Provided herein are compositions (e.g., pharmaceutical compositions, nutraceutical compositions, foods, beverages, cosmetic compositions, diet supplements) comprising deuterated caffeine. The provided compositions may be useful for treating and/or preventing various diseases and conditions, such as obesity, causing weight loss, increasing metabolic rate, reducing appetite, increasing energy expenditure, increasing urine output, increasing sodium excretion, reducing edema, a pain disorder, apnea, hypotension, an encephalopathy, a neurological or psychiatric disorder, and an inflammatory disorder.

RELATED APPLICATIONS

This application claims priority under 35 U.S.C. § 119(e) to U.S.Provisional Application, U.S. Ser. No. 62/861,517, filed on Jun. 14,2019, which is incorporated herein by reference.

BACKGROUND

Caffeine is a central nervous system (CNS) stimulant belonging to themethylxanthine chemical class. It is the world's most widely consumedpsychoactive drug. Caffeine affects several biological processes. Themost prominent is reversibly blocking the action of adenosine on theadenosine receptor, thus, preventing the onset of drowsiness and fatigueinduced by adenosine. It is also known that caffeine stimulates portionsof the autonomic nervous system. In addition to its anti-drowsinesseffect, caffeine has also been shown to positively impact learning,memory, reaction time, wakefulness, concentration, and motorcoordination. Caffeine is also useful in treating bronchopulmonarydysplasia in premature infants, improving weight gain during therapy,and reducing the incidence of cerebral palsy, in addition to reducinglanguage and cognitive delays. Additionally, caffeine has demonstratedpromising results in treating orthostatic hypotension, hypoxic-ischemicencephalopathy (HIE), and delaying the progression of Alzheimer'sdisease. Furthermore, caffeine citrate, marketed under the brand name,CAFCIT®, is approved by the FDA for the treatment of apnea ofprematurity in neonates.

However, despite the positive attributes discussed above, caffeinesuffers from some significant physical and psychological adverse effectsthat limit its use. Caffeine can increase blood pressure, affectgastrointestinal motility and gastric secretion, cause heartpalpitations, cause and worsen anxiety and insomnia, and can beaddictive. It is believed that some or all of the aforementioned adverseeffects can be attributed to caffeine's pharmacokinetic and metabolicprofile. Caffeine ingestion results in a high maximal plasmaconcentration (plasma C_(max)), a short time of maximal plasmaconcentration (T_(max)) after ingestion, short half-life (t_(1/2)), andrapid clearance, mainly by hepatic cytochrome P450 (CYP450)demethylation to afford paraxanthine, theobromine, and theophylline. Inother words, ingestion of caffeine results in a large “spike” incaffeine plasma concentration (i.e., large C_(max)) shortly aftercaffeine ingestion (i.e., short T_(max)) followed by a “crash” incaffeine plasma concentration due to rapid metabolism and clearance. Itis believed that the magnitude of this “spike” and the rapidity of this“crash” are at least partially responsible for the aforementionedadverse effects. Therefore, one approach to mitigate these adverseeffects is to develop compounds and compositions that harness thepositive attributes of caffeine without the negative effects, that is,with pharmacokinetic profiles exhibiting lower C_(max) values, longerhalf-life, and/or longer T_(max) values than caffeine.

SUMMARY OF THE INVENTION

The present invention relates to compositions (e.g., pharmaceuticalcompositions, nutraceutical compositions, foods, beverages, cosmeticcompositions, diet supplements) comprising deuterated caffeine. Incertain embodiments, the composition is suitable for oraladministration. In certain embodiments, the composition is suitable forintravenous (IV) administration. In certain embodiments, the compositionis suitable for topical administration. In certain embodiments, thecomposition is suitable for delivery to the lungs. In certainembodiments, the composition is administered using an electroniccigarette or other vaping device, a nebulizer, a pressurized metereddose inhaler (pMDI), or a dry powder inhaler (DPI). In certainembodiments, the composition is a solid dose composition (e.g., tablet,capsule, granule, powder, sachet, or chewable), solution, gel,suspension, emulsion, shampoo, conditioner, cream, foam, gel, lotion,ointment, transdermal patch, tincture, or paste. Also provided hereinare kits containing the compositions and instructions for use. Furtherprovided herein are use of the compositions described herein fortreating a disease, preventing a disease, treating a condition, and/orpreventing a condition.

The compositions described herein comprise deuterated caffeine (i.e.,wherein at least one of the hydrogen atoms of caffeine is replaced withdeuterium). In certain embodiments, the composition comprises a compoundof Formula (I):

or a pharmaceutically or nutraceutically acceptable salt, hydrate, orsolvate thereof;

wherein each Y is independently hydrogen or deuterium; and

at least one Y is deuterium.

In certain embodiments, the composition comprises about 1 mg to about10,000 mg of a compound of Formula (I), or a pharmaceutically ornutraceutically acceptable salt, hydrate, or solvate thereof. In certainembodiments, the percentage of the amount of the compound of Formula(I), or a pharmaceutically or nutraceutically acceptable salt, hydratesolvate, or prodrug thereof, relative to the total amount of caffeinepresent in the composition ranges from about 5% to about 99%. In anotheraspect, the composition is an oral composition. In another aspect, thecomposition is a solid dose composition (e.g., tablet, capsule, granule,powder, sachet, or chewable). In another aspect, the composition issuitable for intravenous (IV) administration. In another aspect, thecomposition is a topical composition. In another aspect, the compositionis a shampoo, conditioner, cream, foam, gel, lotion, ointment,transdermal patch, tincture, or paste. In another aspect, thecomposition is suitable for inhalation. In another aspect, thecomposition is administered using an electronic cigarette or othervaping device, a nebulizer, a pressurized metered dose inhaler (pMDI),or a dry powder inhaler (DPI). In another aspect, the composition issuitable for buccal administration.

The disclosure further provides a food product comprising deuteratedcaffeine (e.g., a compound of Formula (I)).

The disclosure further provides a beverage (e.g., energy drink, vitaminwater) comprising deuterated caffeine (e.g., a compound of Formula (I)).

The disclosure further provides kits comprising one or more compositionsdescribed herein and instructions for using the composition(s).

The disclosure further provides methods of delivering the compound ofFormula (I), or a pharmaceutically or nutraceutically acceptable salt,hydrate solvate, composition, or prodrug thereof, to a subject in needthereof comprising administering to the subject in need thereof thecompound of Formula (I), or a pharmaceutically or nutraceuticallyacceptable salt, hydrate solvate, composition, or prodrug thereof.

The disclosure further provides methods of treating a disease in asubject in need thereof comprising administering to the subject in needthereof the compound of Formula (I), or a pharmaceutically ornutraceutically acceptable salt, hydrate, solvate, composition, orprodrug thereof.

The disclosure further provides methods of preventing a disease in asubject in need thereof comprising administering to the subject in needthereof the compound of Formula (I), or a pharmaceutically ornutraceutically acceptable salt, hydrate, solvate, composition, orprodrug thereof.

The disclosure further provides methods of treating a condition in asubject in need thereof comprising administering to the subject in needthereof the compound of Formula (I), or a pharmaceutically ornutraceutically acceptable salt, hydrate, solvate, composition, orprodrug thereof.

The disclosure further provides methods of preventing a condition in asubject in need thereof comprising administering to the subject in needthereof the compound of Formula (I), or a pharmaceutically ornutraceutically acceptable salt, hydrate, solvate, composition, orprodrug thereof.

In certain embodiments, the subject is a human. In certain embodiments,the subject is an animal.

In another aspect, the side effects experienced after administration ofa compound of Formula (I), or a pharmaceutically or nutraceuticallyacceptable salt, hydrate, solvate, composition, or prodrug thereof, arereduced relative to the administration of caffeine at an equivalentdose. In another aspect, the side effect is anxiety, insomnia,gastrointestinal issues (e.g., loose stools, diarrhea, stomach ulcers,gastroesophageal reflux, etc.), rhabdomyolysis, addiction, hypertension,rapid heart rate, atrial fibrillation, fatigue, irritability,nervousness, restlessness, nausea, or muscle tremors.

In another aspect, the administration of a compound of Formula (I), or apharmaceutically or nutraceutically acceptable salt, hydrate, solvate,composition, or prodrug thereof, results in an increased duration ofaction, reduction in frequency of administration, increase in patientcompliance and/or ease of use relative to the administration of caffeineat an equivalent dose.

In another aspect, the administration of a compound of Formula (I), or apharmaceutically or nutraceutically acceptable salt, hydrate, solvate,composition, or prodrug thereof, results in a similar relative magnitudeof exposure in plasma and the central nervous system as compared to theadministration of non-isotopically enriched caffeine at an equivalentdose.

The details of one or more embodiments of the present disclosure are setforth herein. Other features, objects, and advantages of the presentdisclosure will be apparent from the Detailed Description, Examples, andClaims.

BRIEF DESCRIPTION OF THE DRAWINGS

The present invention is further described below with reference to thefollowing non-limiting examples and with reference to the followingfigures, in which:

FIG. 1. depicts the mean (+SD) concentrations of caffeine andD9-caffeine (Compound 14) in plasma and brain over 14 hours following anoral (gavage) dose of caffeine or D9-caffeine (Compound 14) to fastedmale Sprague Dawley rats at a dose of 2 mg/kg.

DEFINITIONS

Before further description of the present invention, and in order thatthe invention may be more readily understood, certain terms are firstdefined and collected here for convenience.

The terms “composition” and “formulation” are used interchangeably.

The term “total amount of caffeine” refers to the combined total amountof deuterated caffeine and non-isotopically enriched caffeine.

The amount of an active agent (e.g., deuterated caffeine) or combinationof active agents thereof included in a provided composition, foodproduct, beverage, or nutritional supplement described herein willdepend on the target population. In some embodiments, a providedcomposition, food product, beverage, or nutritional supplement containsan effective amount of an active agent (e.g., deuterated caffeine). Theterm “effective amount,” as used herein, refers to a sufficient amountof the active agent (e.g., deuterated caffeine) to produce a desiredoutcome. The exact amount required will vary from subject to subject,depending on the species, age, general condition of the subject, and theindication. The term “therapeutically effective amount” as used hereinrefers to a sufficient amount of a pharmaceutical or nutraceutical agent(e.g., deuterated caffeine) to achieve the intended purpose, such as,for example, to cause a reduction of symptoms of a condition or disease.A “prophylactically effective amount” refers to a sufficient amount of apharmaceutical or nutraceutical agent (e.g., deuterated caffeine) toachieve the intended purpose, such as prevention of a condition ordisease, one or more symptoms associated with the condition or disease,and/or the recurrence thereof. In certain embodiments, an effectiveamount of a composition, food product, beverage, or nutritionalsupplement is the effective amount of the active agent (e.g., deuteratedcaffeine) included in the composition, food product, beverage, ornutritional supplement.

The term “energy beverage” refers to a type of drink containing sugarand stimulant compounds (e.g., caffeine), which provides mental andphysical stimulation.

The term “vitamin water” refers to water with added natural orartificial flavors, sugar, sweeteners, vitamins, and minerals.

DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS OF THE INVENTION

The present invention relates to compositions comprising deuteratedcaffeine (e.g., a compound of Formula (I)). Also provided herein arekits containing the compositions and instructions for use. Furtherprovided herein are uses of any of the compounds or compositionsdescribed herein for treating a disease, preventing a disease, treatinga condition, preventing a condition, and/or causing an effect.

Compositions, Kits, and Administration

In one aspect, the invention provides a pharmaceutical compositioncomprising a compound of Formula (I):

or a pharmaceutically acceptable salt, hydrate, or solvate thereof;

wherein each Y is independently hydrogen or deuterium; and

at least one Y is deuterium.

In another aspect, the invention provides a nutraceutical compositioncomprising a compound of Formula (I):

or a nutraceutically acceptable salt, hydrate, solvate, or prodrugthereof;

wherein each Y is independently hydrogen or deuterium; and

at least one Y is deuterium.

In another aspect, the invention provides a food product comprising acompound of Formula (I):

or a nutraceutically acceptable salt, hydrate, solvate, or prodrugthereof;

wherein each Y is independently hydrogen or deuterium; and

at least one Y is deuterium.

In another aspect, the invention provides a beverage comprising acompound of Formula (I):

or a nutraceutically acceptable salt, hydrate, solvate, or prodrugthereof;

wherein each Y is independently hydrogen or deuterium; and

at least one Y is deuterium.

In another aspect, the invention provides a nutritional supplementcomprising a compound of Formula (I):

or a nutraceutically acceptable salt, hydrate, solvate, or prodrugthereof;

wherein each Y is independently hydrogen or deuterium; and

at least one Y is deuterium.

In any of the pharmaceutical compositions, nutraceutical compositions,food products, beverages, or nutritional supplements described herein,at least two to eight instances of Y of the compound of Formula (I) aredeuterium. In any of the pharmaceutical compositions, nutraceuticalcompositions, food products, beverages, or nutritional supplementsdescribed herein, at least two instances of Y of the compound of Formula(I) are deuterium. In any of the pharmaceutical compositions,nutraceutical compositions, food products, beverages, or nutritionalsupplements described herein, at least three instances of Y of thecompound of Formula (I) are deuterium In any of the pharmaceuticalcompositions, nutraceutical compositions, food products, beverages, ornutritional supplements described herein, at least four instances of Yof the compound of Formula (I) are deuterium. In any of thepharmaceutical compositions, nutraceutical compositions, food products,beverages, or nutritional supplements described herein, at least fiveinstances of Y of the compound of Formula (I) are deuterium. In any ofthe pharmaceutical compositions, nutraceutical compositions, foodproducts, beverages, or nutritional supplements described herein, atleast six instances of Y of the compound of Formula (I) are deuterium.In any of the pharmaceutical compositions, nutraceutical compositions,food products, beverages, or nutritional supplements described herein,at least seven instances of Y of the compound of Formula (I) aredeuterium. In any of the pharmaceutical compositions, nutraceuticalcompositions, food products, beverages, or nutritional supplementsdescribed herein, at least eight instances of Y of the compound ofFormula (I) are deuterium. In any of the pharmaceutical compositions,nutraceutical compositions, food products, beverages, or nutritionalsupplements described herein, nine instances of Y of the compound ofFormula (I) are deuterium In any of the pharmaceutical compositions,nutraceutical compositions, food products, beverages, or nutritionalsupplements described herein, each Y of the compound of Formula (I) is adeuterium.

In another aspect, the compound of Formula (I), or a pharmaceutically ornutraceutically acceptable salt, hydrate, or solvate thereof, is ofFormula (I-A), (I-B), or (I-C):

or a pharmaceutically or nutraceutically acceptable salt, hydrate, orsolvate thereof.

In another aspect, the compound of Formula (I), or a pharmaceutically ornutraceutically acceptable salt, hydrate, or solvate thereof, is ofFormula (I-D), (I-E), or (I-F):

or a pharmaceutically or nutraceutically acceptable salt, hydrate, orsolvate thereof.

In another aspect, the compound of Formula (I), or a pharmaceutically ornutraceutically acceptable salt, hydrate, or solvate, thereof, is ofFormula (I-G), (I-H), (I-I), (I-J), (I-K), or (I-L):

or a pharmaceutically or nutraceutically acceptable salt, hydrate, orsolvate thereof.

In another aspect, the compound of Formula (I), or a pharmaceutically ornutraceutically acceptable salt, hydrate, or solvate thereof, is ofFormula (I-M), (I-N), (I-O), (I-P), (I-Q), or (I-R):

or a pharmaceutically or nutraceutically acceptable salt, hydrate, orsolvate thereof.

In another aspect, the compound of Formula (I), or a pharmaceutically ornutraceutically acceptable salt, hydrate, or solvate thereof, is ofFormula (I-S), (I-T), or (I-U):

or a pharmaceutically or nutraceutically acceptable salt, hydrate, orsolvate thereof.

In another aspect, the compound of Formula (I), or a pharmaceutically ornutraceutically acceptable salt, hydrate, or solvate thereof, is ofFormula (II-A), (II-B), or (II-C):

or a pharmaceutically or nutraceutically acceptable salt, hydrate, orsolvate thereof.

In another aspect, the compound of Formula (I), or a pharmaceutically ornutraceutically acceptable salt, hydrate, or solvate thereof, is ofFormula (II-D), (II-E), or (II-F):

or a pharmaceutically or nutraceutically acceptable salt, hydrate, orsolvate thereof.

In another aspect, the compound of Formula (I), or a pharmaceutically ornutraceutically acceptable salt, hydrate, or solvate thereof, is ofFormula (II-G), (II-H), or (II-I):

or a pharmaceutically or nutraceutically acceptable salt, hydrate, orsolvate thereof.

In another aspect, the compound of Formula (I), or a pharmaceutically ornutraceutically acceptable salt, hydrate, or solvate thereof, isselected from the group consisting of:

and pharmaceutically or nutraceutically acceptable salts, hydrates, orsolvates thereof.

Another aspect is provided a salt of a compound of Formula (I). Inanother aspect, the salt is an HCl, sulfate, acetate, phosphate,diphosphate, maleate, citrate, mesylate, nitrate, tartrate, or gluconatesalt. In another aspect, the salt is a citrate salt.

In another aspect, the compound of Formula (I), or a pharmaceutically ornutraceutically acceptable salt, hydrate, or solvate thereof, isselected from the group consisting of:

In another aspect, the compound of Formula (I), or a pharmaceutically ornutraceutically acceptable salt, hydrate, or solvate thereof, is

or a pharmaceutically or nutraceutically acceptable salt, hydrate, orsolvate thereof. In another aspect, the compound of Formula (I), or apharmaceutically or nutraceutically acceptable salt, hydrate, or solvatethereof, is

or a pharmaceutically or nutraceutically acceptable salt, hydrate, orsolvate thereof. In another aspect, the compound of Formula (I), or apharmaceutically or nutraceutically acceptable salt, hydrate, or solvatethereof, is

or a pharmaceutically or nutraceutically acceptable salt, hydrate, orsolvate thereof. In another aspect, the compound of Formula (I), or apharmaceutically or nutraceutically acceptable salt, hydrate, or solvatethereof, is

or a pharmaceutically or nutraceutically acceptable salt, hydrate, orsolvate thereof. In another aspect, the compound of Formula (I), or apharmaceutically or nutraceutically acceptable salt, hydrate, or solvatethereof, is

or a pharmaceutically or nutraceutically acceptable salt, hydrate, orsolvate thereof. In another aspect, the compound of Formula (I), or apharmaceutically or nutraceutically acceptable salt, hydrate, or solvatethereof, is

or a pharmaceutically or nutraceutically acceptable salt, hydrate, orsolvate thereof. In another aspect, the compound of Formula (I), or apharmaceutically or nutraceutically acceptable salt, hydrate, or solvatethereof, is

or a pharmaceutically or nutraceutically acceptable salt, hydrate, orsolvate thereof. In another aspect, the compound of Formula (I), or apharmaceutically or nutraceutically acceptable salt, hydrate, or solvatethereof, is

or a pharmaceutically or nutraceutically acceptable salt, hydrate, orsolvate thereof. In another aspect, the compound of Formula (I), or apharmaceutically or nutraceutically acceptable salt, hydrate, or solvatethereof, is

or a pharmaceutically or nutraceutically acceptable salt, hydrate, orsolvate thereof. In another aspect, the compound of Formula (I), or apharmaceutically or nutraceutically acceptable salt, hydrate, or solvatethereof, is

or a pharmaceutically or nutraceutically acceptable salt, hydrate, orsolvate thereof. In another aspect, the compound of Formula (I), or apharmaceutically or nutraceutically acceptable salt, hydrate, or solvatethereof, is

or a pharmaceutically or nutraceutically acceptable salt, hydrate, orsolvate thereof. In another aspect, the compound of Formula (I), or apharmaceutically or nutraceutically acceptable salt, hydrate, or solvatethereof, is

or a pharmaceutically or nutraceutically acceptable salt, hydrate, orsolvate thereof. In another aspect, the compound of Formula (I), or apharmaceutically or nutraceutically acceptable salt, hydrate, or solvatethereof, is

or a pharmaceutically or nutraceutically acceptable salt, hydrate, orsolvate thereof. In another aspect, the compound of Formula (I), or apharmaceutically or nutraceutically acceptable salt, hydrate, or solvatethereof, is

or a pharmaceutically or nutraceutically acceptable salt, hydrate, orsolvate thereof. In another aspect, the compound of Formula (I), or apharmaceutically or nutraceutically acceptable salt, hydrate, or solvatethereof, is

or a pharmaceutically or nutraceutically acceptable salt, hydrate, orsolvate thereof. In another aspect, the compound of Formula (I), or apharmaceutically or nutraceutically acceptable salt, hydrate, or solvatethereof, is

In another aspect, the compound of Formula (I), or a pharmaceutically ornutraceutically acceptable salt, hydrate, or solvate thereof, is

In another aspect, the compound of Formula (I), or a pharmaceutically ornutraceutically acceptable salt, hydrate, or solvate thereof, is

In another aspect, the compound of Formula (I), or a pharmaceutically ornutraceutically acceptable salt, hydrate, or solvate thereof, is

In another aspect, the compound of Formula (I), or a pharmaceutically ornutraceutically acceptable salt, hydrate, or solvate thereof, is

In another aspect, the compound of Formula (I), or a pharmaceutically ornutraceutically acceptable salt, hydrate, or solvate thereof, is

In another aspect, the compound of Formula (I), or a pharmaceutically ornutraceutically acceptable salt, hydrate, or solvate thereof, is

In another aspect, the compound of Formula (I), or a pharmaceutically ornutraceutically acceptable salt, hydrate, or solvate thereof, is

In another aspect, the compound of Formula (I), or a pharmaceutically ornutraceutically acceptable salt, hydrate, or solvate thereof, is

In another aspect, the compound of Formula (I), or a pharmaceutically ornutraceutically acceptable salt, hydrate, or solvate thereof, is

In another aspect, the compound of Formula (I), or a pharmaceutically ornutraceutically acceptable salt, hydrate, or solvate thereof, is

In another aspect, the compound of Formula (I), or a pharmaceutically ornutraceutically acceptable salt, hydrate, or solvate thereof, is

In another aspect, the compound of Formula (I), or a pharmaceutically ornutraceutically acceptable salt, hydrate, or solvate thereof, is

In another aspect, the compound of Formula (I), or a pharmaceutically ornutraceutically acceptable salt, hydrate, or solvate thereof, is

In another aspect, the compound of Formula (I), or a pharmaceutically ornutraceutically acceptable salt, hydrate, or solvate thereof, is

In another aspect, the compound of Formula (I), or a pharmaceutically ornutraceutically acceptable salt, hydrate, or solvate thereof, has anisotopic purity of at least 50.0%, 60.0%, 70.0%, 75.0%, 80.0%, 85.0%,90.0%, 95.0%, 97.0%, 98.0%, 99.0%, 99.5%, 99.7%, 99.8%, or 99.9%. In anyof the pharmaceutical compositions, nutraceutical compositions, foodproducts, beverages, or nutritional supplements described herein, thecompound of Formula (I), or a pharmaceutically or nutraceuticallyacceptable salt, hydrate, or solvate thereof, has an isotopic purity ofat least 50.0%. In another aspect, the compound of Formula (I), or apharmaceutically or nutraceutically acceptable salt, hydrate, or solvatethereof, has an isotopic purity of at least 60.0%. In another aspect,the compound of Formula (I), or a pharmaceutically or nutraceuticallyacceptable salt, hydrate, or solvate thereof, has an isotopic purity ofat least 70.0%. In another aspect, the compound of Formula (I), or apharmaceutically or nutraceutically acceptable salt, hydrate, or solvatethereof, has an isotopic purity of at least 75.0%. In another aspect,the compound of Formula (I), or a pharmaceutically or nutraceuticallyacceptable salt, hydrate, or solvate thereof, has an isotopic purity ofat least 80.0%. In another aspect, the compound of Formula (I), or apharmaceutically or nutraceutically acceptable salt, hydrate, or solvatethereof, has an isotopic purity of at least 85.0%. In another aspect,the compound of Formula (I), or a pharmaceutically or nutraceuticallyacceptable salt, hydrate, or solvate thereof, has an isotopic purity ofat least 90.0%. In another aspect, the compound of Formula (I), or apharmaceutically or nutraceutically acceptable salt, hydrate, or solvatethereof, has an isotopic purity of at least 95.0%. In another aspect,the compound of Formula (I), or a pharmaceutically or nutraceuticallyacceptable salt, hydrate, or solvate thereof, has an isotopic purity ofat least 97.0%. In another aspect, the compound of Formula (I), or apharmaceutically or nutraceutically acceptable salt, hydrate, or solvatethereof, has an isotopic purity of at least 98.0%. In another aspect,the compound of Formula (I), or a pharmaceutically or nutraceuticallyacceptable salt, hydrate, or solvate thereof, has an isotopic purity ofat least 99.0%. In another aspect, the compound of Formula (I), or apharmaceutically or nutraceutically acceptable salt, hydrate, or solvatethereof, has an isotopic purity of at least 99.5%. In another aspect,the compound of Formula (I), or a pharmaceutically or nutraceuticallyacceptable salt, hydrate, or solvate thereof, has an isotopic purity ofat least 99.7%. In another aspect, the compound of Formula (I), or apharmaceutically or nutraceutically acceptable salt, hydrate, or solvatethereof, has an isotopic purity of at least 99.9%. In another aspect,the compound of Formula (I), or a pharmaceutically or nutraceuticallyacceptable salt, hydrate, or solvate thereof, is suitable foradministration to a human or animal. In another aspect, the compound ofFormula (I), or a pharmaceutically or nutraceutically acceptable salt,hydrate, or solvate thereof, is produced and tested in compliance withthe Good Manufacturing Practice (GMP) requirements.

In another aspect, any of the pharmaceutical compositions, nutraceuticalcompositions, food products, beverages, or nutritional supplementsdescribed herein comprises about 1 mg to about 10,000 mg of the compoundof Formula (I), or a pharmaceutically or nutraceutically acceptablesalt, hydrate, or solvate thereof. In another aspect, any of thepharmaceutical compositions, nutraceutical compositions, food products,beverages, or nutritional supplements described herein comprises about 1mg to about 5,000 mg of the compound of Formula (I), or apharmaceutically or nutraceutically acceptable salt, hydrate, or solvatethereof. In another aspect, any of the pharmaceutical compositions,nutraceutical compositions, food products, beverages, or nutritionalsupplements described herein comprises about 1 mg to about 1000 mg ofthe compound of Formula (I), or a pharmaceutically or nutraceuticallyacceptable salt, hydrate, or solvate thereof. In another aspect, thepharmaceutical composition, nutraceutical composition, food product,beverage, or nutritional supplement comprises about 1 mg to about 800 mgof the compound of Formula (I), or a pharmaceutically or nutraceuticallyacceptable salt, hydrate, or solvate thereof. In another aspect, thepharmaceutical composition, nutraceutical composition, food product,beverage, or nutritional supplement comprises about 1 mg to about 600 mgof the compound of Formula (I), or a pharmaceutically or nutraceuticallyacceptable salt, hydrate, or solvate thereof. In another aspect, thepharmaceutical composition, nutraceutical composition, food product,beverage, or nutritional supplement comprises about 1 mg to about 400 mgof the compound of Formula (I), or a pharmaceutically or nutraceuticallyacceptable salt, hydrate, or solvate thereof. In another aspect, thepharmaceutical composition, nutraceutical composition, food product,beverage, or nutritional supplement comprises about 1 mg to about 300 mgof the compound of Formula (I), or a pharmaceutically or nutraceuticallyacceptable salt, hydrate, or solvate thereof. In another aspect, thepharmaceutical composition, nutraceutical composition, food product,beverage, or nutritional supplement comprises about 1 mg to about 250 mgof the compound of Formula (I), or a pharmaceutically or nutraceuticallyacceptable salt, hydrate, or solvate thereof. In another aspect, thepharmaceutical composition, nutraceutical composition, food product,beverage, or nutritional supplement comprises about 1 mg to about 200 mgof the compound of Formula (I), or a pharmaceutically or nutraceuticallyacceptable salt, hydrate, or solvate thereof. In another aspect, thepharmaceutical composition, nutraceutical composition, food product,beverage, or nutritional supplement comprises about 1 mg to about 125 mgof the compound of Formula (I), or a pharmaceutically or nutraceuticallyacceptable salt, hydrate, or solvate thereof. In another aspect, thepharmaceutical composition, nutraceutical composition, food product,beverage, or nutritional supplement comprises about 5 mg to about 75 mgof the compound of Formula (I), or a pharmaceutically or nutraceuticallyacceptable salt, hydrate, or solvate thereof. In another aspect, thepharmaceutical composition, nutraceutical composition, food product,beverage, or nutritional supplement comprises about 10 mg to about 200mg of the compound of Formula (I), or a pharmaceutically ornutraceutically acceptable salt, hydrate, or solvate thereof. In anotheraspect, the pharmaceutical composition, nutraceutical composition, foodproduct, beverage, or nutritional supplement comprises about 10 mg toabout 150 mg of the compound of Formula (I), or a pharmaceutically ornutraceutically acceptable salt, hydrate, or solvate thereof. In anotheraspect the pharmaceutical composition, nutraceutical composition, foodproduct, beverage, or nutritional supplement comprises about 10 mg toabout 100 mg of the compound of Formula (I), or a pharmaceutically ornutraceutically acceptable salt, hydrate, or solvate thereof. In anotheraspect, the pharmaceutical composition, nutraceutical composition, foodproduct, beverage, or nutritional supplement comprises about 10 mg toabout 75 mg of the compound of Formula (I), or a pharmaceutically ornutraceutically acceptable salt, hydrate, or solvate thereof. In anotheraspect, the pharmaceutical composition, nutraceutical composition, foodproduct, beverage, or nutritional supplement comprises about 10 mg toabout 50 mg of the compound of Formula (I), or a pharmaceutically ornutraceutically acceptable salt, hydrate, or solvate thereof. In anotheraspect, the pharmaceutical composition, nutraceutical composition, foodproduct, beverage, or nutritional supplement comprises about 20 mg toabout 200 mg of the compound of Formula (I), or a pharmaceutically ornutraceutically acceptable salt, hydrate, or solvate thereof. In anotheraspect, the pharmaceutical composition, nutraceutical composition, foodproduct, beverage, or nutritional supplement comprises about 20 mg toabout 150 mg of the compound of Formula (I), or a pharmaceutically ornutraceutically acceptable salt, hydrate, or solvate thereof. In anotheraspect, the pharmaceutical composition, nutraceutical composition, foodproduct, beverage, or nutritional supplement comprises about 20 mg toabout 100 mg of the compound of Formula (I), or a pharmaceutically ornutraceutically acceptable salt, hydrate, or solvate thereof. In anotheraspect, the pharmaceutical composition, nutraceutical composition, foodproduct, beverage, or nutritional supplement comprises about 20 mg toabout 75 mg of the compound of Formula (I), or a pharmaceutically ornutraceutically acceptable salt, hydrate, or solvate thereof. In anotheraspect, the pharmaceutical composition, nutraceutical composition, foodproduct, beverage, or nutritional supplement comprises about 20 mg toabout 50 mg of the compound of Formula (I), or a pharmaceutically ornutraceutically acceptable salt, hydrate, or solvate thereof.

In another aspect, any of the pharmaceutical compositions, nutraceuticalcompositions, food products, beverages, or nutritional supplementsdescribed herein comprises about 1 mg/ml to about 100 mg/ml of thecompound of Formula (I), or a pharmaceutically or nutraceuticallyacceptable salt, hydrate, or solvate thereof. In another aspect thepharmaceutical composition, nutraceutical composition, food product,beverage, or nutritional supplement comprises about 1 mg/ml to about 75mg/ml of the compound of Formula (I), or a pharmaceutically ornutraceutically acceptable salt, hydrate, or solvate thereof. In anotheraspect, the pharmaceutical composition, nutraceutical composition, foodproduct, beverage, or nutritional supplement comprises about 1 mg/ml toabout 50 mg/ml of the compound of Formula (I), or a pharmaceutically ornutraceutically acceptable salt, hydrate, or solvate thereof. In anotheraspect, the pharmaceutical composition, nutraceutical composition, foodproduct, beverage, or nutritional supplement comprises about 1 mg/ml toabout 25 mg/ml of the compound of Formula (I), or a pharmaceutically ornutraceutically acceptable salt, hydrate, or solvate thereof. In anotheraspect, the pharmaceutical composition, nutraceutical composition, foodproduct, beverage, or nutritional supplement comprises about 2 mg/ml toabout 100 mg/ml of the compound of Formula (I), or a pharmaceutically ornutraceutically acceptable salt, hydrate, or solvate thereof. In anotheraspect, the pharmaceutical composition, nutraceutical composition, foodproduct, beverage, or nutritional supplement comprises about 2 mg/ml toabout 75 mg/ml of the compound of Formula (I), or a pharmaceutically ornutraceutically acceptable salt, hydrate, or solvate thereof. In anotheraspect, the pharmaceutical composition, nutraceutical composition, foodproduct, beverage, or nutritional supplement comprises about 2 mg/ml toabout 50 mg/ml of the compound of Formula (I), or a pharmaceutically ornutraceutically acceptable salt, hydrate, or solvate thereof. In anotheraspect, the pharmaceutical composition, nutraceutical composition, foodproduct, beverage, or nutritional supplement comprises about 2 mg/ml toabout 25 mg/ml of the compound of Formula (I), or a pharmaceutically ornutraceutically acceptable salt, hydrate, or solvate thereof. In anotheraspect the pharmaceutical composition, nutraceutical composition, foodproduct, beverage, or nutritional supplement comprises about 2 mg/ml toabout 15 mg/ml of the compound of Formula (I), or a pharmaceutically ornutraceutically acceptable salt, hydrate, or solvate thereof. In anotheraspect, the pharmaceutical composition, nutraceutical composition, foodproduct, beverage, or nutritional supplement comprises about 5 mg/ml toabout 100 mg/ml of the compound of Formula (I), or a pharmaceutically ornutraceutically acceptable salt, hydrate, or solvate thereof. In anotheraspect, the pharmaceutical composition, nutraceutical composition, foodproduct, beverage, or nutritional supplement comprises about 5 mg/ml toabout 75 mg/ml of the compound of Formula (I), or a pharmaceutically ornutraceutically acceptable salt, hydrate, or solvate thereof. In anotheraspect, the pharmaceutical composition, nutraceutical composition, foodproduct, beverage, or nutritional supplement comprises about 5 mg/ml toabout 50 mg/ml of the compound of Formula (I), or a pharmaceutically ornutraceutically acceptable salt, hydrate, or solvate thereof. In anotheraspect, the pharmaceutical composition, nutraceutical composition, foodproduct, beverage, or nutritional supplement comprises about 5 mg/ml toabout 25 mg/ml of the compound of Formula (I), or a pharmaceutically ornutraceutically acceptable salt, hydrate, or solvate thereof. In anotheraspect, the pharmaceutical composition, nutraceutical composition, foodproduct, beverage, or nutritional supplement comprises about 5 mg/ml toabout 15 mg/ml of the compound of Formula (I), or a pharmaceutically ornutraceutically acceptable salt, hydrate, or solvate thereof. In anotheraspect, the pharmaceutical or nutraceutical composition may compriseabout 10 mg/ml to about 100 mg/ml of the compound of Formula (I), or apharmaceutically or nutraceutically acceptable salt, hydrate, or solvatethereof. In another aspect, the pharmaceutical or nutraceuticalcomposition may comprise about 10 mg/ml to about 75 mg/ml of thecompound of Formula (I), or a pharmaceutically or nutraceuticallyacceptable salt, hydrate, or solvate thereof. In another aspect, thepharmaceutical or nutraceutical composition may comprise about 10 mg/mlto about 50 mg/ml of the compound of Formula (I), or a pharmaceuticallyor nutraceutically acceptable salt, hydrate, or solvate thereof. Inanother aspect, the pharmaceutical or nutraceutical composition maycomprise about 10 mg/ml to about 25 mg/ml of the compound of Formula(I), or a pharmaceutically or nutraceutically acceptable salt, hydrate,or solvate thereof.

In any of the pharmaceutical compositions, nutraceutical compositions,food products, beverages, or nutritional supplements described herein,the percentage of the amount of the compound of Formula (I), or apharmaceutically or nutraceutically acceptable salt, hydrate, or solvatethereof, relative to the total amount of caffeine present in thecomposition, food product, beverage, or nutritional supplement rangesfrom about 1% to about 99%. In another aspect, the percentage of theamount of the compound of Formula (I), or a pharmaceutically ornutraceutically acceptable salt, hydrate, or solvate thereof, relativeto the total amount of caffeine present in the composition, foodproduct, beverage, or nutritional supplement ranges from about 10% toabout 99%. In another aspect, the percentage of the amount of thecompound of Formula (I), or a pharmaceutically or nutraceuticallyacceptable salt, hydrate, or solvate thereof, relative to the totalamount of caffeine present in the composition, food product, beverage,or nutritional supplement ranges from about 10% to about 90%. In anotheraspect, the percentage of the amount of the compound of Formula (I), ora pharmaceutically or nutraceutically acceptable salt, hydrate, orsolvate thereof, relative to the total amount of caffeine present in thecomposition, food product, beverage, or nutritional supplement rangesfrom about 10% to about 80%. In another aspect, the percentage of theamount of the compound of Formula (I), or a pharmaceutically ornutraceutically acceptable salt, hydrate, or solvate thereof, relativeto the total amount of caffeine present in the composition, foodproduct, beverage, or nutritional supplement ranges from about 10% toabout 70%. In another aspect, the percentage of the amount of thecompound of Formula (I), or a pharmaceutically or nutraceuticallyacceptable salt, hydrate, or solvate thereof, relative to the totalamount of caffeine present in the composition, food product, beverage,or nutritional supplement ranges from about 10% to about 60%. In anotheraspect, the percentage of the amount of the compound of Formula (I), ora pharmaceutically or nutraceutically acceptable salt, hydrate, orsolvate thereof, relative to the total amount of caffeine present in thecomposition, food product, beverage, or nutritional supplement rangesfrom about 10% to about 50%. In another aspect, the percentage of theamount of the compound of Formula (I), or a pharmaceutically ornutraceutically acceptable salt, hydrate, or solvate thereof, relativeto the total amount of caffeine present in the composition, foodproduct, beverage, or nutritional supplement ranges from about 10% toabout 40%. In another aspect, the percentage of the amount of thecompound of Formula (I), or a pharmaceutically or nutraceuticallyacceptable salt, hydrate, or solvate thereof, relative to the totalamount of caffeine present in the composition, food product, beverage,or nutritional supplement ranges from about 10% to about 25%. In anotheraspect, the percentage of the amount of the compound of Formula (I), ora pharmaceutically or nutraceutically acceptable salt, hydrate, orsolvate thereof, relative to the total amount of caffeine present in thecomposition, food product, beverage, or nutritional supplement rangesfrom about 25% to about 99%. In another aspect, the percentage of theamount of the compound of Formula (I), or a pharmaceutically ornutraceutically acceptable salt, hydrate, or solvate thereof, relativeto the total amount of caffeine present in the composition, foodproduct, beverage, or nutritional supplement ranges from about 25% toabout 90%. In another aspect, the percentage of the amount of thecompound of Formula (I), or a pharmaceutically or nutraceuticallyacceptable salt, hydrate, or solvate thereof, relative to the totalamount of caffeine present in the composition, food product, beverage,or nutritional supplement ranges from about 25% to about 80%. In anotheraspect, the percentage of the amount of the compound of Formula (I), ora pharmaceutically or nutraceutically acceptable salt, hydrate, orsolvate thereof, relative to the total amount of caffeine present in thecomposition, food product, beverage, or nutritional supplement rangesfrom about 25% to about 70%. In another aspect, the percentage of theamount of the compound of Formula (I), or a pharmaceutically ornutraceutically acceptable salt, hydrate, or solvate thereof, relativeto the total amount of caffeine present in the composition, foodproduct, beverage, or nutritional supplement ranges from about 25% toabout 60%. In another aspect, the percentage of the amount of thecompound of Formula (I), or a pharmaceutically or nutraceuticallyacceptable salt, hydrate, or solvate thereof, relative to the totalamount of caffeine present in the composition, food product, beverage,or nutritional supplement ranges from about 25% to about 50%. In anotheraspect, the percentage of the amount of the compound of Formula (I), ora pharmaceutically or nutraceutically acceptable salt, hydrate, orsolvate thereof, relative to the total amount of caffeine present in thecomposition, food product, beverage, or nutritional supplement rangesfrom about 25% to about 40%. In another aspect, the percentage of theamount of the compound of Formula (I), or a pharmaceutically ornutraceutically acceptable salt, hydrate, or solvate thereof, relativeto the total amount of caffeine present in the composition, foodproduct, beverage, or nutritional supplement ranges from about 30% toabout 99%. In another aspect, the percentage of the amount of thecompound of Formula (I), or a pharmaceutically or nutraceuticallyacceptable salt, hydrate, or solvate thereof, relative to the totalamount of caffeine present in the composition, food product, beverage,or nutritional supplement ranges from about 30% to about 90%. In anotheraspect, the percentage of the amount of the compound of Formula (I), ora pharmaceutically or nutraceutically acceptable salt, hydrate, orsolvate thereof, relative to the total amount of caffeine present in thecomposition, food product, beverage, or nutritional supplement rangesfrom about 30% to about 80%. In another aspect, the percentage of theamount of the compound of Formula (I), or a pharmaceutically ornutraceutically acceptable salt, hydrate, or solvate thereof, relativeto the total amount of caffeine present in the composition, foodproduct, beverage, or nutritional supplement ranges from about 30% toabout 70%. In another aspect, the percentage of the amount of thecompound of Formula (I), or a pharmaceutically or nutraceuticallyacceptable salt, hydrate, or solvate thereof, relative to the totalamount of caffeine present in the composition, food product, beverage,or nutritional supplement ranges from about 30% to about 60%. In anotheraspect, the percentage of the amount of the compound of Formula (I), ora pharmaceutically or nutraceutically acceptable salt, hydrate, orsolvate thereof, relative to the total amount of caffeine present in thecomposition, food product, beverage, or nutritional supplement rangesfrom about 30% to about 50%. In another aspect, the percentage of theamount of the compound of Formula (I), or a pharmaceutically ornutraceutically acceptable salt, hydrate, or solvate thereof, relativeto the total amount of caffeine present in the composition, foodproduct, beverage, or nutritional supplement ranges from about 40% toabout 99%. In another aspect, the percentage of the amount of thecompound of Formula (I), or a pharmaceutically or nutraceuticallyacceptable salt, hydrate, or solvate thereof, relative to the totalamount of caffeine present in the composition, food product, beverage,or nutritional supplement ranges from about 40% to about 90%. In anotheraspect, the percentage of the amount of the compound of Formula (I), ora pharmaceutically or nutraceutically acceptable salt, hydrate, orsolvate thereof, relative to the total amount of caffeine present in thecomposition, food product, beverage, or nutritional supplement rangesfrom about 40% to about 80%. In another aspect, the percentage of theamount of the compound of Formula (I), or a pharmaceutically ornutraceutically acceptable salt, hydrate, or solvate thereof, relativeto the total amount of caffeine present in the composition, foodproduct, beverage, or nutritional supplement ranges from about 40% toabout 70%. In another aspect, the percentage of the amount of thecompound of Formula (I), or a pharmaceutically or nutraceuticallyacceptable salt, hydrate, or solvate thereof, relative to the totalamount of caffeine present in the composition, food product, beverage,or nutritional supplement ranges from about 40% to about 60%. In anotheraspect, the percentage of the amount of the compound of Formula (I), ora pharmaceutically or nutraceutically acceptable salt, hydrate, orsolvate thereof, relative to the total amount of caffeine present in thecomposition, food product, beverage, or nutritional supplement rangesfrom about 40% to about 50%. In another aspect, the percentage of theamount of the compound of Formula (I), or a pharmaceutically ornutraceutically acceptable salt, hydrate, or solvate thereof, relativeto the total amount of caffeine present in the composition, foodproduct, beverage, or nutritional supplement ranges from about 50% toabout 99%. In another aspect, the percentage of the amount of thecompound of Formula (I), or a pharmaceutically or nutraceuticallyacceptable salt, hydrate, or solvate thereof, relative to the totalamount of caffeine present in the composition, food product, beverage,or nutritional supplement ranges from about 50% to about 90%. In anotheraspect, the percentage of the amount of the compound of Formula (I), ora pharmaceutically or nutraceutically acceptable salt, hydrate, orsolvate thereof, relative to the total amount of caffeine present in thecomposition, food product, beverage, or nutritional supplement rangesfrom about 50% to about 80%. In another aspect, the percentage of theamount of the compound of Formula (I), or a pharmaceutically ornutraceutically acceptable salt, hydrate, or solvate thereof, relativeto the total amount of caffeine present in the composition, foodproduct, beverage, or nutritional supplement ranges from about 50% toabout 70%. In another aspect, the percentage of the amount of thecompound of Formula (I), or a pharmaceutically or nutraceuticallyacceptable salt, hydrate, or solvate thereof, relative to the totalamount of caffeine present in the composition, food product, beverage,or nutritional supplement ranges from about 50% to about 60%.

In another aspect, the compound of Formula (I), or a pharmaceutically ornutraceutically acceptable salt, hydrate, or solvate thereof, isincluded in an amount from about 0.001% to 50% based on the weight ofall the components of the composition, food product, beverage, ornutritional supplement. In certain embodiments, the compound of Formula(I), or a pharmaceutically or nutraceutically acceptable salt, hydrate,or solvate thereof, is included in an amount from about 0.1% to 5%(e.g., 0.1% to 1%, 1% to 5%) based on the weight of all the componentsof the composition, food product, beverage, or nutritional supplement.In certain embodiments, the compound of Formula (I), or apharmaceutically or nutraceutically acceptable salt, hydrate, or solvatethereof, is included in an amount from about 5% to 20% based on theweight of all the components of the composition, food product, beverage,or nutritional supplement. In certain embodiments, the compound ofFormula (I), or a pharmaceutically or nutraceutically acceptable salt,hydrate, or solvate thereof, is included in an amount from about 20% to50% based on the weight of all the components of the composition, foodproduct, beverage, or nutritional supplement.

It will be understood that the total daily usage of the pharmaceuticalcomposition described herein may be decided by an attending physicianwithin the scope of sound medical judgment, and will depend safety andtoxicity profile of the components of the pharmaceutical composition.The specific therapeutically effective dose level for any particularpatient or organism will depend upon a variety of factors including thedisorder being treated and the severity of the disorder; the clinicalstudies results, the activity of the specific compound employed; thespecific pharmaceutical composition employed; the age, body weight,general health, sex and diet of the patient; the time of administration,route of administration, and rate of excretion of the specific compoundemployed; the duration of the treatment; drugs used in combination orcoincidental with the specific compound employed; and like factors wellknown in the medical arts (see, for example, Goodman and Gilman's, ThePharmacological Basis of Therapeutics, Tenth Edition, A. Gilman, J.Hardman, and L. Limbird, eds., McGraw-Hill Press, 155-173, 2001).

In another aspect, any of the pharmaceutical compositions describedherein may be suitable for oral administration, parenteral (e.g.,intravenous (IV)) administration, topical administration, inhalation,buccal administration, or for delivery to the lungs. In another aspect,the pharmaceutical composition is suitable for oral administration. Inanother aspect, the pharmaceutical composition is suitable forparenteral administration. In another aspect, the pharmaceuticalcomposition is suitable for intravenous (IV) administration. In anotheraspect, the pharmaceutical composition is suitable for topicaladministration. In another aspect, the pharmaceutical composition issuitable for delivery to the lungs.

In another aspect, any of the nutraceutical compositions describedherein may be suitable for oral administration.

In another aspect, the composition is a cosmetic composition. In anotheraspect, the cosmetic composition is suitable for topical administration.

In another aspect, any of the pharmaceutical or nutraceuticalcompositions described herein suitable for oral administration may be asolid dose composition. In another aspect, the solid dose compositionmay be a tablet, capsule, granule, powder, sachet, or chewable.

In another aspect, any of the pharmaceutical, nutraceutical, or cosmeticcompositions described herein suitable for topical administration may bea shampoo, conditioner, shampoo, conditioner, cream, foam, gel, lotion,ointment, transdermal patch, tincture, or paste.

In another aspect, any of the pharmaceutical compositions describedherein suitable for delivery to the lungs may be administered using anelectronic cigarette or other vaping device, a nebulizer, a pressurizedmetered dose inhaler (pMDI), or a dry powder inhaler (DPI).

In another aspect, any of the pharmaceutical, nutraceutical, or cosmeticcompositions described herein may further comprise a pharmaceutically ornutraceutically acceptable carrier.

In another aspect, any of the pharmaceutical, nutraceutical, or cosmeticcompositions described herein may further comprise an additional agent.In another aspect, the additional agent refers to natural or syntheticcompound(s) capable of activity or other direct effect in the diagnosis,cure, mitigation, treatment or prevention of disease or to affect thestructure and function of the body. In any of the foregoing embodiments,a provided composition may contain one or more active agents, including,but not limiting to pharmaceutical agent that belong to differentBiopharmaceutics Classification System (BCS), for example, from BCSclass I, II, III or IV, and/or peptides, and/or vaccines and/or nucleicacid-based products and/or immunologic agents and/or phytopharmaceuticalagents and/or nutraceutical agents and/or cosmetic agents and/orsupplements. In certain embodiments, the active agent is a smallmolecule (e.g., when the molecular weight is lower than 500, 800, 1000,or 1500, g/mol). In certain embodiments, the active agent is a drugapproved by the U.S. Food and Drug Administration and/or the EuropeanMedicines Agency.

In the present invention, each additional agent may be incorporated inthe composition. Depending upon the qualitative and quantitativecomposition of the formulation chosen, the additional agent(s) may bereleased from the composition over a period of time (i.e. sustainedrelease) or immediately. The present invention can be used in thetreatment of both humans and animals.

In another aspect, the additional agent is ergotamine, ananti-inflammatory agent, a steroid, a barbiturate, an opioid analgesic,or a combination thereof. In another aspect, any of the hydrogen atomsin ergotamine, the anti-inflammatory agent, the steroid, thebarbiturate, or the opioid analgesic may be replaced with deuterium. Inanother aspect, the anti-inflammatory agent is a cyclooxygenase-3(COX-3) inhibitor, a non-steroidal anti-inflammatory drug (NSAID), or acyclooxygenase-2 (COX-2) inhibitor.

In another aspect, the NSAID is ibuprofen, naproxen, sulindac,ketoprofen, tolmetin, etodolac, fenoprofen, diclofenac, flurbiprofen,piroxicam, ketorolac, indomethacin, nabumetone, oxaprozin, mefanamicacid, or diflunisal.

In another aspect, the opioid analgesic is codeine, fentanyl,hydrocodone, hydromorphone, meperidine, methadone, morphine, oroxycodone.

In another aspect, the barbiturate is secobarbital, mephobarbital,pentobarbital, butabarbital, phenobarbital, or amobarbital.

In another aspect, the COX-2 inhibitor is celecoxib, valdecoxib,rofecoxib, or etoricoxib.

In another aspect, the COX-3 inhibitor is acetaminophen, phenacetin,antipyrine, or dipyrone.

In another aspect, the percentage of deuterium (i.e. the percentage ofhydrogen atoms replaced by deuterium atoms) in ergotamine, theanti-inflammatory agent, the steroid, the barbiturate, or the opioidanalgesic is at least 5%. In another aspect, the percentage of deuteriumin ergotamine, the anti-inflammatory agent, the steroid, thebarbiturate, or the opioid analgesic is at least 10%. In another aspect,the percentage of deuterium in ergotamine, the anti-inflammatory agent,the steroid, the barbiturate, or the opioid analgesic is at least 15%.In another aspect, the percentage of deuterium in ergotamine, theanti-inflammatory agent, the steroid, the barbiturate, or the opioidanalgesic is at least 20%. In another aspect, the percentage ofdeuterium in ergotamine, the anti-inflammatory agent, the steroid, thebarbiturate, or the opioid analgesic is at least 25%. In another aspect,the percentage of deuterium in ergotamine, the anti-inflammatory agent,the steroid, the barbiturate, or the opioid analgesic is at least 30%.In another aspect, the percentage of deuterium in ergotamine, theanti-inflammatory agent, the steroid, the barbiturate, or the opioidanalgesic is at least 40%. In another aspect, the percentage ofdeuterium in ergotamine, the anti-inflammatory agent, the steroid, thebarbiturate, or the opioid analgesic is at least 50%. In another aspect,the percentage of deuterium in ergotamine, the anti-inflammatory agent,the steroid, the barbiturate, or the opioid analgesic is at least 60%.In another aspect, the percentage of deuterium in ergotamine, theanti-inflammatory agent, the steroid, the barbiturate, or the opioidanalgesic is at least 70%. In another aspect, the percentage ofdeuterium in ergotamine, the anti-inflammatory agent, the steroid, thebarbiturate, or the opioid analgesic is at least 80%. In another aspect,the percentage of deuterium in ergotamine, the anti-inflammatory agent,the steroid, the barbiturate, or the opioid analgesic is at least 90%.In another aspect, the percentage of deuterium in ergotamine, theanti-inflammatory agent, the steroid, the barbiturate, or the opioidanalgesic is at least 95%. In another aspect, the percentage ofdeuterium in ergotamine, the anti-inflammatory agent, the steroid, thebarbiturate, or the opioid analgesic is at least 97%. In another aspect,the percentage of deuterium in ergotamine, the anti-inflammatory agent,the steroid, the barbiturate, or the opioid analgesic is at least 99%.

In certain embodiments, the composition further comprises a sweetener.Sweeteners can be used to improve palatability and are usuallyclassified as natural or artificial. A sweetener may be a naturalsweetener or artificial sweetener. Exemplary natural sweeteners include,but are not limited to, dextrose, fructose, glucose, liquid glucose,maltose, rebiana, glycyrrhizin, thaumatin, sorbitol, mannitol, isomalt,glycerol, maltitol, xylitol, and erythritol. Exemplary artificialsweeteners include, but are not limited to, saccharin, cyclamate,aspartame, acesulfame-K, sucralose, alitame and neotame. In certainembodiments, sucralose is used as a sweetener. In certain embodiments,one or combination of neohespiridin dihydrochalcone, glycerol and/orsucralose are used as sweeteners. In some embodiments, the concentrationof the sweetener in the composition is between 0.01% and 5%, inclusive,by weight. In some embodiments, the concentration of the sweetener inthe composition is between 0.01% and 1%, inclusive, by weight. In someembodiments, the concentration of the sweetener in the composition isbetween 0.5% and 1%, inclusive, by weight. In certain embodiments, thecomposition further comprises sucralose. In certain embodiments, thecomposition further comprises sucralose as about 0.01-0.25% based on thedry weight of all the components of the composition.

In certain embodiments, a composition further comprises a colorant. Acolorant can be added to enhance the aesthetic appeal of thecomposition, especially when formulation ingredients or drugs arepresented in a non-solution form. Generally, any colorant could beadded, such as for example FD&C pigments (for example, blue n^(o)1, bluen^(o)2, red n^(o)3, red n^(o)40, yellow n^(o)5, or yellow n^(o) 6).Exemplary colorants include, but are not limited to annatto extract,dehydrated beets (beet powder), canthaxanthin, caramel,β-apo-8′-carotenal, β-carotene, cochineal extract, carmine, sodiumcopper chlorophyllin, toasted partially defatted cooked cottonseedflour, ferrous gluconate, ferrous lactate, grape color extract, grapeskin extract (enocianina), synthetic iron oxide, fruit juice, vegetablejuice, carrot oil, paprika, paprika oleoresin, mica-based pearlescentpigments, riboflavin, saffron, spirulina extract, titanium dioxide,tomato lycopene extract; tomato lycopene concentrate, turmeric, turmericoleoresin, alumina (dried aluminum hydroxide), calcium carbonate,potassium sodium copper chlorophyllin (chlorophyllin-copper complex),dihydroxyacetone, bismuth oxychloride, synthetic iron oxide, ferricammonium ferrocyanide, ferric ferrocyanide, chromium hydroxide green,chromium oxide greens, guanine, pyrophyllite, mica, talc, aluminumpowder, bronze powder, copper powder, zinc oxide, bismuth citrate,disodium EDTA-copper, guaiazulene, henna, lead acetate, pyrophyllite,silver, ultramarines, manganese violet, luminescent zinc sulfide, FD&CBlue No. 1, FD&C Blue No. 2, FD&C Green No. 3, Orange B, Citrus Red No.2, FD&C Red No. 3, FD&C Red No. 40, FD&C Yellow No. 5, FD&C Yellow No.6, D&C Blue No. 4, D&C Green No. 5, D&C Green No. 6, D&C Green No. 8,D&C Orange No. 4, D&C Orange No. 5, D&C Orange No. 10, D&C Orange No.11, FD&C Red No. 4, D&C Red No. 6, D&C Red No. 7, D&C Red No. 17, D&CRed No. 21, D&C Red No. 22, D&C Red No. 27, D&C Red No. 28, D&C Red No.30, D&C Red No. 31, D&C Red No. 33, D&C Red No. 34, D&C Red No. 36, D&CRed No. 39, D&C Violet No. 2, D&C Yellow No. 7, Ext. D&C Yellow No. 7,D&C Yellow No. 8, D&C Yellow No. 10, D&C Yellow No. 11, D&C Black No. 2,D&C Black No. 3, D&C Brown No. 1, and Ext. D&C Violet No. 2. In certainembodiments, a colorant represents 0.001% to about 0.5% based on theweight of all the components of the composition. In some embodiments,the concentration of the colorant in the composition is between 0.001%and 5%, inclusive, by weight. In some embodiments, the concentration ofthe colorant in the composition is between 0.001% and 1%, inclusive, byweight.

In certain embodiments, a provided composition further comprises aflavoring agent. In certain embodiments, the selection of a suitableflavoring agent to be added depends on the original taste sensation ofthe composition, including metallic, acidic, alkaline, salty, sweet,bitter and sour taste sensation. Certain flavoring agents, alone or incombination, mask specific taste sensations. For example, metallic tastecould be masked with, but not limited to, flavoring agents based onberry fruits, grape, and/or peppermint. For example, acidic taste couldbe masked with, but not limited to, flavoring agents based on lemon,lime, grapefruit, orange, cherry, and/or strawberry. For example,alkaline taste could be masked with, but not limited to, flavoringagents based on aniseed, caramel, passion fruit, peach and/or banana.For example, salty taste could be masked with, but not limited to,flavoring agents based on butterscotch, caramel, hazelnut, spicy, maple,apricot, apple, peach, vanilla, and/or wintergreen mint. For example,bitter taste could be masked with, but not limited to, flavoring agentsbased on licorice, passion fruit, coffee, chocolate, peppermint,grapefruit, cherry, peach, raspberry, wild cherry, walnut, mint and/oranise. For example, sweet taste could be masked with, but not limitedto, flavoring agents based on grape, cream, caramel, banana, vanillaand/or fruit berry. For example, sour taste could be masked with, butnot limited to, flavoring agents based on citrus flavors, licorice,root, bear and/or raspberry. Flavoring agents can be used alone or incombination and its selection will be dependent also upon the targetpopulation and any other substance (e.g., a pharmaceutical ornutraceutical agent) incorporated in the composition. The perception ofthe flavoring agent changes from individual to individual and also withage: typically a geriatric population will prefer mint or orange flavorswhereas younger populations tend to prefer flavors like fruit punch,raspberry, etc. Generally, the amount of flavoring agent needed to maskan unpleasant taste or improve taste overall will depend not only on thecomposition of the formulation but also on the flavor type and itsstrength.

In certain embodiments, a flavoring agent is a palatable flavor that hasa long shelf life and which does not crystallize or precipitate out ofthe composition upon storage. In certain embodiments, flavoring agentsmay be natural flavors, derived from various parts of the plants likeleaves, fruits and flowers, or synthetic flavor oils or powders.Exemplary flavor oils that may be used in or as flavoring agentsinclude, but are not limited to, peppermint oil, cinnamon oil, spearmintoil, and oil of nutmeg. Exemplary fruity flavors that may be used in oras flavoring agents include, but are not limited to, vanilla, cocoa,coffee, chocolate and citrus. Exemplary fruit essence flavors that maybe used in or as flavoring agents include, but are not limited to,apple, raspberry, cherry, and pineapple. The amount of flavoring agentadded can vary with the flavor employed. In some embodiments, theconcentration of the flavoring agent in the composition is between about0% and 5%, by weight. In some embodiments, the concentration of theflavoring agent in the composition is between 0.001% and 5%, inclusive,by weight. In some embodiments, the concentration of the flavoring agentin the composition is between 0.1% and 1%, inclusive, by weight. In someembodiments, the concentration of the flavoring agent in the compositionis between 0.5% and 1%, inclusive, by weight.

In certain embodiments, a provided composition further comprisestaste-masking. Taste-masking agents can be added to ameliorate thegeneral organoleptic characteristics of the compositions. In certainembodiments, taste-masking agents may be used to mask unpleasant tasteof some components. The main taste sensations include metallic, acidic,alkaline, salty, sweet, bitter and sour. Exemplary of taste-maskingagents include, but are not limited to, menthol, peppermint oil,L-Menthol, cyclodextrins, glycerol, maltodextrins, ion-exchange resins,amino acids, gelatin, gelatinized starch, liposomes, lecithin orlecithin-like substances and salts. The amount of taste-masking addedcan vary with the taste-masking employed. In certain embodiments, thetaste-masking agent comprises about 0% to about 50% based on the dryweight of all the components of the composition. In certain embodiments,the taste-masking agent represents 0% to about 5% based on the dryweight of all the components of the composition.

In another aspect, a provided composition further comprises a coolingagent. Cooling agents may also be added in order to improve theafter-taste of the composition. Exemplary cooling agents include, butare not limited to, neohesperidine dihydrochalcone, menthol flavor,L-Menthol and some polyol sugars which are widely used for this purpose.Other components can also be added that should compete with sensorystimuli, such as Cremophor (which is used to coat the surface proteinreceptors), or saline solutions (e.g. sodium chloride, which competeswithin channel receptors with the bitter stimuli to reduce the overallperception of bitterness). In certain embodiments, the cooling agents inthe composition is one or a combination of neohesperidinedihydrochalcone, menthol and/or polyol sugar. In certain embodiments,the mucoadhesive composition further comprises cooling agents of about0% to about 5% based on the weight of all the components of thecomposition. In certain embodiments, the mucoadhesive compositionfurther comprises cooling agents as about 0.001% to about 2.5% based onthe weight of all the components of the composition.

In certain embodiments, a provided composition further comprises one ormore preservatives. The preservative employed in the invention can beany preservative, as long as does not negate other desirable propertiesof the composition. Example of a preservative is an antimicrobialpreservative that is used to prevent or inhibit the growth ofmicro-organisms in the composition. Exemplary preservative agentsinclude, but are not limited to, C₃-C₈ alcohols, phenylethyl alcohol,chlorbutanol, p-hydroxybenzoic, acid esters, benzathonium chloride andbenzalkonium chloride, benzoic acid, propyl galate, methylparaben,propylparaben, sorbic acid, sodium benzoate and/or potassium sorbate.The amount of preservative agent added can vary with the preservativeagent employed. In certain embodiments, a preservative agent representsabout 0% to about 45% based on the weight of all the components of thecomposition. In certain embodiments, a preservative agent representsabout 0% to about 1% (e.g., 0.025% to 0.2%) based on the weight of allthe components of the composition.

In certain embodiments, a provided composition (e.g., cosmetic orpharmaceutical composition) further comprises penetration enhancementadditives. Penetration enhancers effectively increase permeability ofactive agents and/or composition excipients. Preferably, penetrationenhancement additives are compatible with the active agents and otherformulation excipients, pharmacologically inert, nontoxic andinexpensive. Exemplary penetration enhancement additives include, butare not limited to, bile salts, surfactants, fatty acids andderivatives, glycerides, chelators, salicylates, polymers, or othercompounds. Exemplary of bile salts that act as Penetration enhancementadditives include, but are not limited to, Sodium glycocholate, sodiumdeoxycholate, sodium taurocholate, sodium fusidate, sodiumglycodeoxycholate, sodium taurodihydrofusidate. Exemplary of surfactantsthat act as penetration enhancement additives include, but are notlimited to, sodium lauryl sulfate, brij1-35, lysophosphatidylcholine,dioctyl sodium sulfosuccinate, laurenth-9, polysorbate-80,polyethyleneglycol-8-laurate, glyceryl monolaurate. Exemplary of fattyacids and derivatives that act as Penetration enhancement additivesinclude, but are not limited to, sorbitan laurate, sodium caprate,sucrose palmitate, lauroyl choline, sodium myristate, palmitoylcarnitine. Exemplary of glycerides that act as penetration enhancementadditives include, but are not limited to phospholipids, monohexanoin,medium chain glycerides. Exemplary of chelators that act as penetrationenhancement additives include, but are not limited to ethylene diaminetetraacetate (EDTA), disodium EDTA. Exemplary of salicylates that act aspenetration enhancement additives include, but are not limited tosalicylic acid, sodium methoxysalicylate, acetyl salicylic acid.Exemplary of polymers that act as penetration enhancement additivesinclude, but are not limited to chitosan, polycarbophil, sodiumcarboxymethylcellulose and their derivatives. Exemplary of othercompounds that act as Penetration enhancement additives include, but arenot limited to cyclodextrins, benzalkonium chloride, phenothiazines,nitric acid donors, menthol, zonula occluden toxin, poly-1-arginines,soybean derivative glucosides, citicholine, α-acid derivatives. Theamount of penetration enhancement additives added can vary with thePenetration enhancement additives agent employed.

In one aspect, the invention provides a beverage comprising deuteratedcaffeine. In another aspect, the beverage comprises one or more ofwater, flavoring agent(s), sweetener(s), vitamins, minerals, co-factors,proteins, lipids, peptides, and amino acids.

In another aspect, the invention provides a beverage comprising waterand a compound of Formula (I):

or a pharmaceutically or nutraceutically acceptable salt, hydrate, orsolvate thereof;

wherein each Y is independently hydrogen or deuterium; and

at least one Y is deuterium.

In another aspect, the beverage further comprises one or more of aflavoring and a sweetener.

In another aspect, the beverage further comprises one or more ofvitamins, minerals, co-factors, proteins, lipids, peptides, and aminoacids.

In another aspect, the beverage is an energy beverage. In anotheraspect, the energy beverage further comprises one or more of water,taurine, citicoline, vitamin B6, vitamin B12, folic acid, niacinamide,glucuronolactone, N-acetyl-L-tyrosine, L-phenylalanine, and malic acid.

In another aspect, the beverage is a vitamin water. In another aspect,the vitamin water further comprises one or more of water, vitamin C,vitamin B5, vitamin B6, vitamin B12, magnesium, and pantothenic acid.

In another aspect, the beverage is a coffee (decaffeinated or comprisingnon-isotopically enriched caffeine) that is enhanced or “spiked” withthe compound of Formula (I), or a pharmaceutically or nutraceuticallyacceptable salt, hydrate, or solvate thereof.

In another aspect, the beverage comprises about 1 mg to about 1000 mg ofthe compound of Formula (I), or a pharmaceutically or nutraceuticallyacceptable salt, hydrate, or solvate thereof. In another aspect, thebeverage comprises about 1 mg to about 800 mg of the compound of Formula(I), or a pharmaceutically or nutraceutically acceptable salt, hydrate,or solvate thereof. In another aspect, the beverage comprises about 1 mgto about 600 mg of the compound of Formula (I), or a pharmaceutically ornutraceutically acceptable salt, hydrate, or solvate thereof. In anotheraspect, the beverage comprises about 1 mg to about 400 mg of thecompound of Formula (I), or a pharmaceutically or nutraceuticallyacceptable salt, hydrate, or solvate thereof. In another aspect, thebeverage comprises about 1 mg to about 300 mg of the compound of Formula(I), or a pharmaceutically or nutraceutically acceptable salt, hydrate,or solvate thereof. In another aspect, the beverage comprises about 1 mgto about 250 mg of the compound of Formula (I), or a pharmaceutically ornutraceutically acceptable salt, hydrate, or solvate thereof. In anotheraspect, the beverage comprises about 1 mg to about 200 mg of thecompound of Formula (I), or a pharmaceutically or nutraceuticallyacceptable salt, hydrate, or solvate thereof. In another aspect, thebeverage comprises about 1 mg to about 125 mg of the compound of Formula(I), or a pharmaceutically or nutraceutically acceptable salt, hydrate,or solvate thereof. In another aspect, the beverage comprises about 5 mgto about 75 mg of the compound of Formula (I), or a pharmaceutically ornutraceutically acceptable salt, hydrate, or solvate thereof. In anotheraspect, the beverage comprises about 10 mg to about 200 mg of thecompound of Formula (I), or a pharmaceutically or nutraceuticallyacceptable salt, hydrate, or solvate thereof. In another aspect, thebeverage comprises about 10 mg to about 150 mg of the compound ofFormula (I), or a pharmaceutically or nutraceutically acceptable salt,hydrate, or solvate thereof. In another aspect, the beverage comprisesabout 10 mg to about 100 mg of the compound of Formula (I), or apharmaceutically or nutraceutically acceptable salt, hydrate, or solvatethereof. In another aspect, the beverage comprises about 10 mg to about75 mg of the compound of Formula (I), or a pharmaceutically ornutraceutically acceptable salt, hydrate, or solvate thereof. In anotheraspect, the beverage comprises about 10 mg to about 50 mg of thecompound of Formula (I), or a pharmaceutically or nutraceuticallyacceptable salt, hydrate, or solvate thereof. In another aspect, thebeverage comprises about 20 mg to about 200 mg of the compound ofFormula (I), or a pharmaceutically or nutraceutically acceptable salt,hydrate, or solvate thereof. In another aspect, the beverage comprisesabout 20 mg to about 150 mg of the compound of Formula (I), or apharmaceutically or nutraceutically acceptable salt, hydrate, or solvatethereof. In another aspect, the beverage comprises about 20 mg to about100 mg of the compound of Formula (I), or a pharmaceutically ornutraceutically acceptable salt, hydrate, or solvate thereof. In anotheraspect, the beverage comprises about 20 mg to about 75 mg of thecompound of Formula (I), or a pharmaceutically or nutraceuticallyacceptable salt, hydrate, or solvate thereof. In another aspect, thebeverage comprises about 20 mg to about 50 mg of the compound of Formula(I), or a pharmaceutically or nutraceutically acceptable salt, hydrate,or solvate thereof.

In another aspect, any of the beverage comprises about 1 mg/ml to about100 mg/ml of the compound of Formula (I), or a pharmaceutically ornutraceutically acceptable salt, hydrate, or solvate thereof. In anotheraspect, the beverage comprises about 1 mg/ml to about 75 mg/ml of thecompound of Formula (I), or a pharmaceutically or nutraceuticallyacceptable salt, hydrate, or solvate thereof. In another aspect, thebeverage comprises about 1 mg/ml to about 50 mg/ml of the compound ofFormula (I), or a pharmaceutically or nutraceutically acceptable salt,hydrate, or solvate thereof. In another aspect, the beverage comprisesabout 1 mg/ml to about 25 mg/ml of the compound of Formula (I), or apharmaceutically or nutraceutically acceptable salt, hydrate, or solvatethereof. In another aspect, the beverage comprises about 2 mg/ml toabout 100 mg/ml of the compound of Formula (I), or a pharmaceutically ornutraceutically acceptable salt, hydrate, or solvate thereof. In anotheraspect, the beverage comprises about 2 mg/ml to about 75 mg/ml of thecompound of Formula (I), or a pharmaceutically or nutraceuticallyacceptable salt, hydrate, or solvate thereof. In another aspect, thebeverage comprises about 2 mg/ml to about 50 mg/ml of the compound ofFormula (I), or a pharmaceutically or nutraceutically acceptable salt,hydrate, or solvate thereof. In another aspect, the beverage comprisesabout 2 mg/ml to about 25 mg/ml of the compound of Formula (I), or apharmaceutically or nutraceutically acceptable salt, hydrate, or solvatethereof. In another aspect, the beverage comprises about 2 mg/ml toabout 15 mg/ml of the compound of Formula (I), or a pharmaceutically ornutraceutically acceptable salt, hydrate, or solvate thereof. In anotheraspect, the beverage comprises about 5 mg/ml to about 100 mg/ml of thecompound of Formula (I), or a pharmaceutically or nutraceuticallyacceptable salt, hydrate, or solvate thereof. In another aspect, thebeverage comprises about 5 mg/ml to about 75 mg/ml of the compound ofFormula (I), or a pharmaceutically or nutraceutically acceptable salt,hydrate, or solvate thereof. In another aspect, the beverage comprisesabout 5 mg/ml to about 50 mg/ml of the compound of Formula (I), or apharmaceutically or nutraceutically acceptable salt, hydrate, or solvatethereof. In another aspect, the beverage comprises about 5 mg/ml toabout 25 mg/ml of the compound of Formula (I), or a pharmaceutically ornutraceutically acceptable salt, hydrate, or solvate thereof. In anotheraspect, the beverage comprises about 5 mg/ml to about 15 mg/ml of thecompound of Formula (I), or a pharmaceutically or nutraceuticallyacceptable salt, hydrate, or solvate thereof. In another aspect, thebeverage comprises about 10 mg/ml to about 100 mg/ml of the compound ofFormula (I), or a pharmaceutically or nutraceutically acceptable salt,hydrate, or solvate thereof. In another aspect, the beverage comprisesabout 10 mg/ml to about 75 mg/ml of the compound of Formula (I), or apharmaceutically or nutraceutically acceptable salt, hydrate, or solvatethereof. In another aspect, the beverage comprises about 10 mg/ml toabout 50 mg/ml of the compound of Formula (I), or a pharmaceutically ornutraceutically acceptable salt, hydrate, or solvate thereof. In anotheraspect, the beverage comprises about 10 mg/ml to about 25 mg/ml of thecompound of Formula (I), or a pharmaceutically or nutraceuticallyacceptable salt, hydrate, or solvate thereof.

In another aspect, the percentage of the amount of the compound ofFormula (I), or a pharmaceutically or nutraceutically acceptable salt,hydrate, or solvate thereof, relative to the total amount of caffeinepresent in the beverage ranges from about 1% to about 99%. In anotheraspect, the percentage of the amount of the compound of Formula (I), ora pharmaceutically or nutraceutically acceptable salt, hydrate, orsolvate thereof, relative to the total amount of caffeine present in thebeverage ranges from about 10% to about 99%. In another aspect, thepercentage of the amount of the compound of Formula (I), or apharmaceutically or nutraceutically acceptable salt, hydrate, or solvatethereof, relative to the total amount of caffeine present in thebeverage ranges from about 10% to about 90%. In another aspect, thepercentage of the amount of the compound of Formula (I), or apharmaceutically or nutraceutically acceptable salt, hydrate, or solvatethereof, relative to the total amount of caffeine present in thebeverage ranges from about 10% to about 80%. In another aspect, thepercentage of the amount of the compound of Formula (I), or apharmaceutically or nutraceutically acceptable salt, hydrate, or solvatethereof, relative to the total amount of caffeine present in thebeverage ranges from about 10% to about 70%. In another aspect, thepercentage of the amount of the compound of Formula (I), or apharmaceutically or nutraceutically acceptable salt, hydrate, or solvatethereof, relative to the total amount of caffeine present in thebeverage ranges from about 10% to about 60%. In another aspect, thepercentage of the amount of the compound of Formula (I), or apharmaceutically or nutraceutically acceptable salt, hydrate, or solvatethereof, relative to the total amount of caffeine present in thebeverage ranges from about 10% to about 50%. In another aspect, thepercentage of the amount of the compound of Formula (I), or apharmaceutically or nutraceutically acceptable salt, hydrate, or solvatethereof, relative to the total amount of caffeine present in thebeverage ranges from about 10% to about 40%. In another aspect, thepercentage of the amount of the compound of Formula (I), or apharmaceutically or nutraceutically acceptable salt, hydrate, or solvatethereof, relative to the total amount of caffeine present in thebeverage ranges from about 10% to about 25%. In another aspect, thepercentage of the amount of the compound of Formula (I), or apharmaceutically or nutraceutically acceptable salt, hydrate, or solvatethereof, relative to the total amount of caffeine present in thebeverage ranges from about 25% to about 99%. In another aspect, thepercentage of the amount of the compound of Formula (I), or apharmaceutically or nutraceutically acceptable salt, hydrate, or solvatethereof, relative to the total amount of caffeine present in thebeverage ranges from about 25% to about 90%. In another aspect, thepercentage of the amount of the compound of Formula (I), or apharmaceutically or nutraceutically acceptable salt, hydrate, or solvatethereof, relative to the total amount of caffeine present in thebeverage ranges from about 25% to about 80%. In another aspect, thepercentage of the amount of the compound of Formula (I), or apharmaceutically or nutraceutically acceptable salt, hydrate, or solvatethereof, relative to the total amount of caffeine present in thebeverage ranges from about 25% to about 70%. In another aspect, thepercentage of the amount of the compound of Formula (I), or apharmaceutically or nutraceutically acceptable salt, hydrate, or solvatethereof, relative to the total amount of caffeine present in thebeverage ranges from about 25% to about 60%. In another aspect, thepercentage of the amount of the compound of Formula (I), or apharmaceutically or nutraceutically acceptable salt, hydrate, or solvatethereof, relative to the total amount of caffeine present in thebeverage ranges from about 25% to about 50%. In another aspect, thepercentage of the amount of the compound of Formula (I), or apharmaceutically or nutraceutically acceptable salt, hydrate, or solvatethereof, relative to the total amount of caffeine present in thebeverage ranges from about 25% to about 40%. In another aspect, thepercentage of the amount of the compound of Formula (I), or apharmaceutically or nutraceutically acceptable salt, hydrate, or solvatethereof, relative to the total amount of caffeine present in thebeverage ranges from about 30% to about 99%. In another aspect, thepercentage of the amount of the compound of Formula (I), or apharmaceutically or nutraceutically acceptable salt, hydrate, or solvatethereof, relative to the total amount of caffeine present in thebeverage ranges from about 30% to about 90%. In another aspect, thepercentage of the amount of the compound of Formula (I), or apharmaceutically or nutraceutically acceptable salt, hydrate, or solvatethereof, relative to the total amount of caffeine present in thebeverage ranges from about 30% to about 80%. In another aspect, thepercentage of the amount of the compound of Formula (I), or apharmaceutically or nutraceutically acceptable salt, hydrate, or solvatethereof, relative to the total amount of caffeine present in thebeverage ranges from about 30% to about 70%. In another aspect, thepercentage of the amount of the compound of Formula (I), or apharmaceutically or nutraceutically acceptable salt, hydrate, or solvatethereof, relative to the total amount of caffeine present in thebeverage ranges from about 30% to about 60%. In another aspect, thepercentage of the amount of the compound of Formula (I), or apharmaceutically or nutraceutically acceptable salt, hydrate, or solvatethereof, relative to the total amount of caffeine present in thebeverage ranges from about 30% to about 50%. In another aspect, thepercentage of the amount of the compound of Formula (I), or apharmaceutically or nutraceutically acceptable salt, hydrate, or solvatethereof, relative to the total amount of caffeine present in thebeverage ranges from about 40% to about 99%. In another aspect, thepercentage of the amount of the compound of Formula (I), or apharmaceutically or nutraceutically acceptable salt, hydrate, or solvatethereof, relative to the total amount of caffeine present in thebeverage ranges from about 40% to about 90%. In another aspect, thepercentage of the amount of the compound of Formula (I), or apharmaceutically or nutraceutically acceptable salt, hydrate, or solvatethereof, relative to the total amount of caffeine present in thebeverage ranges from about 40% to about 80%. In another aspect, thepercentage of the amount of the compound of Formula (I), or apharmaceutically or nutraceutically acceptable salt, hydrate, or solvatethereof, relative to the total amount of caffeine present in thebeverage ranges from about 40% to about 70%. In another aspect, thepercentage of the amount of the compound of Formula (I), or apharmaceutically or nutraceutically acceptable salt, hydrate, or solvatethereof, relative to the total amount of caffeine present in thebeverage ranges from about 40% to about 60%. In another aspect, thepercentage of the amount of the compound of Formula (I), or apharmaceutically or nutraceutically acceptable salt, hydrate, or solvatethereof, relative to the total amount of caffeine present in thebeverage ranges from about 40% to about 50%. In another aspect, thepercentage of the amount of the compound of Formula (I), or apharmaceutically or nutraceutically acceptable salt, hydrate, or solvatethereof, relative to the total amount of caffeine present in thebeverage ranges from about 50% to about 99%. In another aspect, thepercentage of the amount of the compound of Formula (I), or apharmaceutically or nutraceutically acceptable salt, hydrate, or solvatethereof, relative to the total amount of caffeine present in thebeverage ranges from about 50% to about 90%. In another aspect, thepercentage of the amount of the compound of Formula (I), or apharmaceutically or nutraceutically acceptable salt, hydrate, or solvatethereof, relative to the total amount of caffeine present in thebeverage ranges from about 50% to about 80%. In another aspect, thepercentage of the amount of the compound of Formula (I), or apharmaceutically or nutraceutically acceptable salt, hydrate, or solvatethereof, relative to the total amount of caffeine present in thebeverage ranges from about 50% to about 70%. In another aspect, thepercentage of the amount of the compound of Formula (I), or apharmaceutically or nutraceutically acceptable salt, hydrate, or solvatethereof, relative to the total amount of caffeine present in thebeverage ranges from about 50% to about 60%.

In another aspect, the invention provides a food product comprising acompound of Formula (I):

or a pharmaceutically or nutraceutically acceptable salt, hydrate, orsolvate thereof;

wherein each Y is independently hydrogen or deuterium; and

at least one Y is deuterium.

In another aspect, the food product is any item that is to be processed,partially processed, or unprocessed for consumption. In another aspect,the food product is an energy bar, energy gel, pre-work out supplement,or other performance enhancing supplements. In another aspect, the foodproduct is a food additive. In another aspect, the food product is anenergy bar. In another aspect, the energy bar further comprises one ormore of sugar, cocoa butter, chocolate liquor, whole milk powder, soylecithin, vanilla extract, caramel, peanuts, peanut butter, almonds,oats, molasses, cinnamon, salt, and soybean oil.

In another aspect, the food product may comprise about 1 mg to about1000 mg of the compound of Formula (I), or a pharmaceutically ornutraceutically acceptable salt, hydrate, or solvate thereof. In anotheraspect, the food product may comprise about 1 mg to about 800 mg of thecompound of Formula (I), or a pharmaceutically or nutraceuticallyacceptable salt, hydrate, or solvate thereof. In another aspect, thefood product may comprise about 1 mg to about 600 mg of the compound ofFormula (I), or a pharmaceutically or nutraceutically acceptable salt,hydrate, or solvate thereof. In another aspect, the food product maycomprise about 1 mg to about 400 mg of the compound of Formula (I), or apharmaceutically or nutraceutically acceptable salt, hydrate, or solvatethereof. In another aspect, the food product may comprise about 1 mg toabout 300 mg of the compound of Formula (I), or a pharmaceutically ornutraceutically acceptable salt, hydrate, or solvate thereof. In anotheraspect, the food product may comprise about 1 mg to about 250 mg of thecompound of Formula (I), or a pharmaceutically or nutraceuticallyacceptable salt, hydrate, or solvate thereof. In another aspect, thefood product may comprise about 1 mg to about 200 mg of the compound ofFormula (I), or a pharmaceutically or nutraceutically acceptable salt,hydrate, or solvate thereof. In another aspect, the food product maycomprise about 1 mg to about 125 mg of the compound of Formula (I), or apharmaceutically or nutraceutically acceptable salt, hydrate, or solvatethereof. In another aspect, the food product may comprise about 5 mg toabout 75 mg of the compound of Formula (I), or a pharmaceutically ornutraceutically acceptable salt, hydrate, or solvate thereof. In anotheraspect, the food product may comprise about 10 mg to about 200 mg of thecompound of Formula (I), or a pharmaceutically or nutraceuticallyacceptable salt, hydrate, or solvate thereof. In another aspect, thefood product may comprise about 10 mg to about 150 mg of the compound ofFormula (I), or a pharmaceutically or nutraceutically acceptable salt,hydrate, or solvate thereof. In another aspect, the food product maycomprise about 10 mg to about 100 mg of the compound of Formula (I), ora pharmaceutically or nutraceutically acceptable salt, hydrate, orsolvate thereof. In another aspect, the food product may comprise about10 mg to about 75 mg of the compound of Formula (I), or apharmaceutically or nutraceutically acceptable salt, hydrate, or solvatethereof. In another aspect, the food product may comprise about 10 mg toabout 50 mg of the compound of Formula (I), or a pharmaceutically ornutraceutically acceptable salt, hydrate, or solvate thereof. In anotheraspect, the food product may comprise about 20 mg to about 200 mg of thecompound of Formula (I), or a pharmaceutically or nutraceuticallyacceptable salt, hydrate, or solvate thereof. In another aspect, thefood product may comprise about 20 mg to about 150 mg of the compound ofFormula (I), or a pharmaceutically or nutraceutically acceptable salt,hydrate, or solvate thereof. In another aspect, the food product maycomprise about 20 mg to about 100 mg of the compound of Formula (I), ora pharmaceutically or nutraceutically acceptable salt, hydrate, orsolvate thereof. In another aspect, the food product may comprise about20 mg to about 75 mg of the compound of Formula (I), or apharmaceutically or nutraceutically acceptable salt, hydrate, or solvatethereof. In another aspect, the food product may comprise about 20 mg toabout 50 mg of the compound of Formula (I), or a pharmaceutically ornutraceutically acceptable salt, hydrate, or solvate thereof.

In another aspect, the percentage of the amount of the compound ofFormula (I), or a pharmaceutically or nutraceutically acceptable salt,hydrate, or solvate thereof, relative to the total amount of caffeinepresent in the food product ranges from about 1% to about 99%. Inanother aspect, the percentage of the amount of the compound of Formula(I), or a pharmaceutically or nutraceutically acceptable salt, hydrate,or solvate thereof, relative to the total amount of caffeine present inthe food product ranges from about 10% to about 99%. In another aspect,the percentage of the amount of the compound of Formula (I), or apharmaceutically or nutraceutically acceptable salt, hydrate, or solvatethereof, relative to the total amount of caffeine present in the foodproduct ranges from about 10% to about 90%. In another aspect, thepercentage of the amount of the compound of Formula (I), or apharmaceutically or nutraceutically acceptable salt, hydrate, or solvatethereof, relative to the total amount of caffeine present in the foodproduct ranges from about 10% to about 80%. In another aspect, thepercentage of the amount of the compound of Formula (I), or apharmaceutically or nutraceutically acceptable salt, hydrate, or solvatethereof, relative to the total amount of caffeine present in the foodproduct ranges from about 10% to about 70%. In another aspect, thepercentage of the amount of the compound of Formula (I), or apharmaceutically or nutraceutically acceptable salt, hydrate, or solvatethereof, relative to the total amount of caffeine present in the foodproduct ranges from about 10% to about 60%. In another aspect, thepercentage of the amount of the compound of Formula (I), or apharmaceutically or nutraceutically acceptable salt, hydrate, or solvatethereof, relative to the total amount of caffeine present in the foodproduct ranges from about 10% to about 50%. In another aspect, thepercentage of the amount of the compound of Formula (I), or apharmaceutically or nutraceutically acceptable salt, hydrate, or solvatethereof, relative to the total amount of caffeine present in the foodproduct ranges from about 10% to about 40%. In another aspect, thepercentage of the amount of the compound of Formula (I), or apharmaceutically or nutraceutically acceptable salt, hydrate, or solvatethereof, relative to the total amount of caffeine present in the foodproduct ranges from about 10% to about 25%. In another aspect, thepercentage of the amount of the compound of Formula (I), or apharmaceutically or nutraceutically acceptable salt, hydrate, or solvatethereof, relative to the total amount of caffeine present in the foodproduct ranges from about 25% to about 99%. In another aspect, thepercentage of the amount of the compound of Formula (I), or apharmaceutically or nutraceutically acceptable salt, hydrate, or solvatethereof, relative to the total amount of caffeine present in the foodproduct ranges from about 25% to about 90%. In another aspect, thepercentage of the amount of the compound of Formula (I), or apharmaceutically or nutraceutically acceptable salt, hydrate, or solvatethereof, relative to the total amount of caffeine present in the foodproduct ranges from about 25% to about 80%. In another aspect, thepercentage of the amount of the compound of Formula (I), or apharmaceutically or nutraceutically acceptable salt, hydrate, or solvatethereof, relative to the total amount of caffeine present in the foodproduct ranges from about 25% to about 70%. In another aspect, thepercentage of the amount of the compound of Formula (I), or apharmaceutically or nutraceutically acceptable salt, hydrate, or solvatethereof, relative to the total amount of caffeine present in the foodproduct ranges from about 25% to about 60%. In another aspect, thepercentage of the amount of the compound of Formula (I), or apharmaceutically or nutraceutically acceptable salt, hydrate, or solvatethereof, relative to the total amount of caffeine present in the foodproduct ranges from about 25% to about 50%. In another aspect, thepercentage of the amount of the compound of Formula (I), or apharmaceutically or nutraceutically acceptable salt, hydrate, or solvatethereof, relative to the total amount of caffeine present in the foodproduct ranges from about 25% to about 40%. In another aspect, thepercentage of the amount of the compound of Formula (I), or apharmaceutically or nutraceutically acceptable salt, hydrate, or solvatethereof, relative to the total amount of caffeine present in the foodproduct ranges from about 30% to about 99%. In another aspect, thepercentage of the amount of the compound of Formula (I), or apharmaceutically or nutraceutically acceptable salt, hydrate, or solvatethereof, relative to the total amount of caffeine present in the foodproduct ranges from about 30% to about 90%. In another aspect, thepercentage of the amount of the compound of Formula (I), or apharmaceutically or nutraceutically acceptable salt, hydrate, or solvatethereof, relative to the total amount of caffeine present in the foodproduct ranges from about 30% to about 80%. In another aspect, thepercentage of the amount of the compound of Formula (I), or apharmaceutically or nutraceutically acceptable salt, hydrate, or solvatethereof, relative to the total amount of caffeine present in the foodproduct ranges from about 30% to about 70%. In another aspect, thepercentage of the amount of the compound of Formula (I), or apharmaceutically or nutraceutically acceptable salt, hydrate, or solvatethereof, relative to the total amount of caffeine present in the foodproduct ranges from about 30% to about 60%. In another aspect, thepercentage of the amount of the compound of Formula (I), or apharmaceutically or nutraceutically acceptable salt, hydrate, or solvatethereof, relative to the total amount of caffeine present in the foodproduct ranges from about 30% to about 50%. In another aspect, thepercentage of the amount of the compound of Formula (I), or apharmaceutically or nutraceutically acceptable salt, hydrate, or solvatethereof, relative to the total amount of caffeine present in the foodproduct ranges from about 40% to about 99%. In another aspect, thepercentage of the amount of the compound of Formula (I), or apharmaceutically or nutraceutically acceptable salt, hydrate, or solvatethereof, relative to the total amount of caffeine present in the foodproduct ranges from about 40% to about 90%. In another aspect, thepercentage of the amount of the compound of Formula (I), or apharmaceutically or nutraceutically acceptable salt, hydrate, or solvatethereof, relative to the total amount of caffeine present in the foodproduct ranges from about 40% to about 80%. In another aspect, thepercentage of the amount of the compound of Formula (I), or apharmaceutically or nutraceutically acceptable salt, hydrate, or solvatethereof, relative to the total amount of caffeine present in the foodproduct ranges from about 40% to about 70%. In another aspect, thepercentage of the amount of the compound of Formula (I), or apharmaceutically or nutraceutically acceptable salt, hydrate, or solvatethereof, relative to the total amount of caffeine present in the foodproduct ranges from about 40% to about 60%. In another aspect, thepercentage of the amount of the compound of Formula (I), or apharmaceutically or nutraceutically acceptable salt, hydrate, or solvatethereof, relative to the total amount of caffeine present in the foodproduct ranges from about 40% to about 50%. In another aspect, thepercentage of the amount of the compound of Formula (I), or apharmaceutically or nutraceutically acceptable salt, hydrate, or solvatethereof, relative to the total amount of caffeine present in the foodproduct ranges from about 50% to about 99%. In another aspect, thepercentage of the amount of the compound of Formula (I), or apharmaceutically or nutraceutically acceptable salt, hydrate, or solvatethereof, relative to the total amount of caffeine present in the foodproduct ranges from about 50% to about 90%. In another aspect, thepercentage of the amount of the compound of Formula (I), or apharmaceutically or nutraceutically acceptable salt, hydrate, or solvatethereof, relative to the total amount of caffeine present in the foodproduct ranges from about 50% to about 80%. In another aspect, thepercentage of the amount of the compound of Formula (I), or apharmaceutically or nutraceutically acceptable salt, hydrate, or solvatethereof, relative to the total amount of caffeine present in the foodproduct ranges from about 50% to about 70%. In another aspect, thepercentage of the amount of the compound of Formula (I), or apharmaceutically or nutraceutically acceptable salt, hydrate, or solvatethereof, relative to the total amount of caffeine present in the foodproduct ranges from about 50% to about 60%.

It will be understood that when a range is recited in the application,the end of the range are specifically disclosed as if specificallyrecited. For example, a range of about 19% to about 99% specificallyinclude a disclosure separately of 19% and separately of 99%.

Also encompassed by the present disclosure are kits (e.g.,pharmaceutical or nutraceutical packs). In certain embodiments, the kitcomprises a pharmaceutical or nutraceutical composition describedherein, and instructions for using the pharmaceutical or nutraceuticalcomposition. In certain embodiments, the kit comprises a firstcontainer, wherein the first container includes the pharmaceutical ornutraceutical composition. In some embodiments, the kit furthercomprises a second container. In certain embodiments, the secondcontainer includes an excipient (e.g., an excipient for dilution orsuspension of the pharmaceutical or nutraceutical composition). Incertain embodiments, the second container includes an additional agent.In some embodiments, the kit further comprises a third container. Incertain embodiments, the third container includes an additional agent.In some embodiments, the pharmaceutical or nutraceutical compositionincluded in the first container and the excipient or additional agent(s)included in the second container are combined to form one unit dosageform. In some embodiments, the pharmaceutical or nutraceuticalcomposition included in the first container, the excipient included inthe second container, and the additional agent included in the thirdcontainer are combined to form one unit dosage form. In certainembodiments, each of the first, second, and third containers isindependently a vial, ampule, bottle, syringe, dispenser package, tube,sprayer, or inhaler. In certain embodiments, at least one of the first,second, and third containers is a sprayer.

In certain embodiments, the instructions are for administering thepharmaceutical or nutraceutical composition to a subject in needthereof. In certain embodiments, the instructions comprise informationrequired by a regulatory agency, such as the U.S. Food and DrugAdministration (FDA) or the European Agency for the Evaluation ofMedicinal Products (EMA). In certain embodiments, the instructionscomprise prescribing information.

Methods of Use and Uses

The present disclosure also provides methods of using the compounds,compositions, beverages, and food products of the present disclosure. Inanother aspect, the present disclosure provides methods of delivering toa subject in need thereof a composition (e.g., an effective amount ofthe composition) (e.g., pharmaceutical composition, nutraceuticalcomposition, cosmetic composition, diet supplement) of the presentdisclosure.

In another aspect, the present disclosure provides methods of treating adisease in a subject in need thereof comprising administering to thesubject in need thereof an effective amount (e.g., therapeuticallyeffective amount) of a compound or composition (e.g., pharmaceutical ornutraceutical composition) of the present disclosure.

In another aspect, the present disclosure provides methods of preventinga disease in a subject in need thereof comprising administering to thesubject in need thereof an effective amount (e.g., therapeuticallyeffective amount) of a compound or composition (e.g., pharmaceutical ornutraceutical composition) of the present disclosure.

In another aspect, provided herein are uses of the compounds orcompositions of the present disclosure in the manufacture of amedicament for use in a method (e.g., method of delivering an activeagent to a subject in need thereof, method of treating a disease in asubject in need thereof, method of preventing a disease in a subject inneed thereof) of the present disclosure.

In another aspect, provided herein are uses of the compounds orcompositions of the present disclosure in a method (e.g., method ofdelivering an active agent to a subject in need thereof, method oftreating a disease in a subject in need thereof, method of preventing adisease in a subject in need thereof) of the present disclosure.

In certain embodiments, the subject is an animal. The animal may be ofeither sex and may be at any stage of development. In certainembodiments, the subject described herein is a human. The human may be achild or an adult. In certain embodiments, the subject is a non-humananimal. In certain embodiments, the subject is a mammal. In certainembodiments, the subject is a non-human mammal. In certain embodiments,the subject is a domesticated animal, such as a dog, cat, cow, pig,horse, sheep, or goat. In certain embodiments, the subject is a dog. Incertain embodiments, the subject is a companion animal, such as a dog orcat. In certain embodiments, the subject is a livestock animal, such asa cow, pig, horse, sheep, or goat. In certain embodiments, the subjectis a zoo animal. In another embodiment, the subject is a researchanimal, such as a rodent (e.g., mouse, rat), dog, pig, or non-humanprimate. In certain embodiments, the animal is a genetically engineeredanimal. In certain embodiments, the animal is a transgenic animal (e.g.,transgenic mice, transgenic pigs). In certain embodiments, a subject inneed thereof is a subject in need of delivery of an active agent or acomposition, a subject in need of treatment of a disease, or a subjectin need of prevention of a disease.

In certain embodiments, the effective amount is effective in treatingthe disease. In certain embodiments, the effective amount is effectivein preventing the disease.

In certain aspects, the disease is an inflammatory disease. The term“inflammatory disease” refers to a disease caused by, resulting from, orresulting in inflammation. The term “inflammatory disease” may alsorefer to a dysregulated inflammatory reaction that causes an exaggeratedresponse by macrophages, granulocytes, and/or T-lymphocytes leading toabnormal tissue damage and/or cell death. An inflammatory disease can beeither an acute or chronic inflammatory condition and can result frominfections or non-infectious causes Inflammatory diseases includeatherosclerosis, arteriosclerosis, autoimmune disorders, multiplesclerosis, systemic lupus erythematosus, polymyalgia rheumatica (PMR),gouty arthritis, degenerative arthritis, tendonitis, bursitis,psoriasis, cystic fibrosis, arthrosteitis, rheumatoid arthritis,inflammatory arthritis, Sjogren's syndrome, giant cell arteritis,progressive systemic sclerosis (scleroderma), ankylosing spondylitis,polymyositis, dermatomyositis, pemphigus, pemphigoid, diabetes (e.g.,Type I), myasthenia gravis, Hashimoto's thyroiditis, Graves' disease,Goodpasture's disease, mixed connective tissue disease, sclerosingcholangitis, inflammatory bowel disease, Crohn's disease, ulcerativecolitis, pernicious anemia, inflammatory dermatoses, usual interstitialpneumonitis (UIP), asbestosis, silicosis, bronchiectasis, berylliosis,talcosis, pneumoconiosis, sarcoidosis, desquamative interstitialpneumonia, lymphoid interstitial pneumonia, giant cell interstitialpneumonia, cellular interstitial pneumonia, extrinsic allergicalveolitis, Wegener's granulomatosis and related forms of angiitis(temporal arteritis and polyarteritis nodosa), inflammatory dermatoses,hepatitis, delayed-type hypersensitivity reactions (e.g., poison ivydermatitis), pneumonia, respiratory tract inflammation, AdultRespiratory Distress Syndrome (ARDS), encephalitis, immediatehypersensitivity reactions, asthma, hayfever, allergies, acuteanaphylaxis, rheumatic fever, glomerulonephritis, pyelonephritis,cellulitis, cystitis, chronic cholecystitis, ischemia (ischemic injury),reperfusion injury, allograft rejection, host-versus-graft rejection,appendicitis, arteritis, blepharitis, bronchiolitis, bronchitis,cervicitis, cholangitis, chorioamnionitis, conjunctivitis,dacryoadenitis, dermatomyositis, endocarditis, endometritis, enteritis,enterocolitis, epicondylitis, epididymitis, fasciitis, fibrositis,gastritis, gastroenteritis, gingivitis, ileitis, iritis, laryngitis,myelitis, myocarditis, nephritis, omphalitis, oophoritis, orchitis,osteitis, otitis, pancreatitis, parotitis, pericarditis, pharyngitis,pleuritis, phlebitis, pneumonitis, proctitis, prostatitis, rhinitis,salpingitis, sinusitis, stomatitis, synovitis, testitis, tonsillitis,urethritis, urocystitis, uveitis, vaginitis, vasculitis, vulvitis,vulvovaginitis, angitis, chronic bronchitis, osteomyelitis, opticneuritis, temporal arteritis, transverse myelitis, necrotizingfasciitis, and necrotizing enterocolitis. An ocular inflammatory diseaseincludes post-surgical inflammation.

In certain aspects, the disease is a neurological disease. In certainembodiments, the disease is a neurological disease. The term“neurological disease” refers to any disease of the nervous system,including diseases that involve the central nervous system (brain,brainstem and cerebellum), the peripheral nervous system (includingcranial nerves), and the autonomic nervous system (parts of which arelocated in both central and peripheral nervous system).Neurodegenerative diseases refer to a type of neurological diseasemarked by the loss of nerve cells, including Alzheimer's disease,Parkinson's disease, amyotrophic lateral sclerosis, tauopathies(including frontotemporal dementia), and Huntington's disease. Examplesof neurological diseases include headache, stupor and coma, dementia,seizure, sleep disorders, trauma, infections, neoplasms,neuro-ophthalmology, movement disorders, demyelinating diseases, spinalcord disorders, and disorders of peripheral nerves, muscle andneuromuscular junctions. Addiction and mental illness, include bipolardisorder and schizophrenia, are also included in the definition ofneurological diseases. Further examples of neurological diseases includeacquired epileptiform aphasia; acute disseminated encephalomyelitis;adrenoleukodystrophy; agenesis of the corpus callosum; agnosia; Aicardisyndrome; Alexander disease; Alpers' disease; alternating hemiplegia;Alzheimer's disease; amyotrophic lateral sclerosis; anencephaly;Angelman syndrome; angiomatosis; anoxia; aphasia; apraxia; arachnoidcysts; arachnoiditis; Arnold-Chiari malformation; arteriovenousmalformation; Asperger syndrome; ataxia telangiectasia; attentiondeficit hyperactivity disorder; autism; autonomic dysfunction; backpain; Batten disease; Behcet's disease; Bell's palsy; benign essentialblepharospasm; benign focal; amyotrophy; benign intracranialhypertension; Binswanger's disease; blepharospasm; Bloch Sulzbergersyndrome; brachial plexus injury; brain abscess; bbrain injury; braintumors (including glioblastoma multiforme); spinal tumor; Brown-Sequardsyndrome; Canavan disease; carpal tunnel syndrome (CTS); causalgia;central pain syndrome; central pontine myelinolysis; cephalic disorder;cerebral aneurysm; cerebral arteriosclerosis; cerebral atrophy; cerebralgigantism; cerebral palsy; Charcot-Marie-Tooth disease;chemotherapy-induced neuropathy and neuropathic pain; Chiarimalformation; chorea; chronic inflammatory demyelinating polyneuropathy(CIDP); chronic pain; chronic regional pain syndrome; Coffin Lowrysyndrome; coma, including persistent vegetative state; congenital facialdiplegia; corticobasal degeneration; cranial arteritis;craniosynostosis; Creutzfeldt-Jakob disease; cumulative traumadisorders; Cushing's syndrome; cytomegalic inclusion body disease(CIBD); cytomegalovirus infection; dancing eyes-dancing feet syndrome;Dandy-Walker syndrome; Dawson disease; De Morsier's syndrome;Dejerine-Klumpke palsy; dementia; dermatomyositis; diabetic neuropathy;diffuse sclerosis; dysautonomia; dysgraphia; dyslexia; dystonias; earlyinfantile epileptic encephalopathy; empty sella syndrome; encephalitis;encephaloceles; encephalotrigeminal angiomatosis; epilepsy; Erb's palsy;essential tremor; Fabry's disease; Fahr's syndrome; fainting; familialspastic paralysis; febrile seizures; Fisher syndrome; Friedreich'sataxia; frontotemporal dementia and other “tauopathies”; Gaucher'sdisease; Gerstmann's syndrome; giant cell arteritis; giant cellinclusion disease; globoid cell leukodystrophy; Guillain-Barre syndrome;HTLV-1 associated myelopathy; Hallervorden-Spatz disease; head injury;headache; hemifacial spasm; hereditary spastic paraplegia; heredopathiaatactica polyneuritiformis; herpes zoster oticus; herpes zoster;Hirayama syndrome; HIV-associated dementia and neuropathy (see alsoneurological manifestations of AIDS); holoprosencephaly; Huntington'sdisease and other polyglutamine repeat diseases; hydranencephaly;hydrocephalus; hypercortisolism; hypoxia; immune-mediatedencephalomyelitis; inclusion body myositis; incontinentia pigmenti;infantile; phytanic acid storage disease; Infantile Refsum disease;infantile spasms; inflammatory myopathy; intracranial cyst; intracranialhypertension; Joubert syndrome; Kearns-Sayre syndrome; Kennedy disease;Kinsbourne syndrome; Klippel Feil syndrome; Krabbe disease;Kugelberg-Welander disease; kuru; Lafora disease; Lambert-Eatonmyasthenic syndrome; Landau-Kleffner syndrome; lateral medullary(Wallenberg) syndrome; learning disabilities; Leigh's disease;Lennox-Gastaut syndrome; Lesch-Nyhan syndrome; leukodystrophy; Lewy bodydementia; lissencephaly; locked-in syndrome; Lou Gehrig's disease (akamotor neuron disease or amyotrophic lateral sclerosis); lumbar discdisease; lyme disease-neurological sequelae; Machado-Joseph disease;macrencephaly; megalencephaly; Melkersson-Rosenthal syndrome; Menieresdisease; meningitis; Menkes disease; metachromatic leukodystrophy;microcephaly; migraine; Miller Fisher syndrome; mini-strokes;mitochondrial myopathies; Mobius syndrome; monomelic amyotrophy; motorneurone disease; moyamoya disease; mucopolysaccharidoses; multi-infarctdementia; multifocal motor neuropathy; multiple sclerosis and otherdemyelinating disorders; multiple system atrophy with posturalhypotension; muscular dystrophy; myasthenia gravis; myelinoclasticdiffuse sclerosis; myoclonic encephalopathy of infants; myoclonus;myopathy; myotonia congenital; narcolepsy; neurofibromatosis;neuroleptic malignant syndrome; neurological manifestations of AIDS;neurological sequelae of lupus; neuromyotonia; neuronal ceroidlipofuscinosis; neuronal migration disorders; Niemann-Pick disease;O'Sullivan-McLeod syndrome; occipital neuralgia; occult spinaldysraphism sequence; Ohtahara syndrome; olivopontocerebellar atrophy;opsoclonus myoclonus; optic neuritis; orthostatic hypotension; overusesyndrome; paresthesia; Parkinson's disease; paramyotonia congenita;paraneoplastic diseases; paroxysmal attacks; Parry Romberg syndrome;Pelizaeus-Merzbacher disease; periodic paralyses; peripheral neuropathy;painful neuropathy and neuropathic pain; persistent vegetative state;pervasive developmental disorders; photic sneeze reflex; phytanic acidstorage disease; Pick's disease; pinched nerve; pituitary tumors;polymyositis; porencephaly; Post-Polio syndrome; postherpetic neuralgia(PHN); postinfectious encephalomyelitis; postural hypotension;Prader-Willi syndrome; primary lateral sclerosis; prion diseases;progressive; hemifacial atrophy; progressive multifocalleukoencephalopathy; progressive sclerosing poliodystrophy; progressivesupranuclear palsy; pseudotumor cerebri; Ramsay-Hunt syndrome (Type Iand Type II); Rasmussen's Encephalitis; reflex sympathetic dystrophysyndrome; Refsum disease; repetitive motion disorders; repetitive stressinjuries; restless legs syndrome; retrovirus-associated myelopathy; Rettsyndrome; Reye's syndrome; Saint Vitus Dance; Sandhoff disease;Schilder's disease; schizencephaly; septo-optic dysplasia; shaken babysyndrome; shingles; Shy-Drager syndrome; Sjogren's syndrome; sleepapnea; Soto's syndrome; spasticity; spina bifida; spinal cord injury;spinal cord tumors; spinal muscular atrophy; stiff-person syndrome;stroke; Sturge-Weber syndrome; subacute sclerosing panencephalitis;subarachnoid hemorrhage; subcortical arteriosclerotic encephalopathy;sydenham chorea; syncope; syringomyelia; tardive dyskinesia; Tay-Sachsdisease; temporal arteritis; tethered spinal cord syndrome; Thomsendisease; thoracic outlet syndrome; tic douloureux; Todd's paralysis;Tourette syndrome; transient ischemic attack; transmissible spongiformencephalopathies; transverse myelitis; traumatic brain injury; tremor;trigeminal neuralgia; tropical spastic paraparesis; tuberous sclerosis;vascular dementia (multi-infarct dementia); vasculitis includingtemporal arteritis; Von Hippel-Lindau Disease (VHL); Wallenberg'ssyndrome; Werdnig-Hoffman disease; West syndrome; whiplash; Williamssyndrome; Wilson's disease; and Zellweger syndrome.

In certain embodiments, the disease is a painful condition. A “painfulcondition” includes neuropathic pain (e.g., peripheral neuropathicpain), central pain, deafferentation pain, chronic pain (e.g., chronicnociceptive pain, and other forms of chronic pain such as post-operativepain, e.g., pain arising after hip, knee, or other replacement surgery),pre-operative pain, stimulus of nociceptive receptors (nociceptivepain), acute pain (e.g., phantom and transient acute pain),noninflammatory pain, inflammatory pain, pain associated with cancer,wound pain, burn pain, postoperative pain, pain associated with medicalprocedures, pain resulting from pruritus, painful bladder syndrome, painassociated with premenstrual dysphoric disorder and/or premenstrualsyndrome, pain associated with chronic fatigue syndrome, pain associatedwith pre-term labor, pain associated with withdrawl symptoms from drugaddiction, joint pain, arthritic pain (e.g., pain associated withcrystalline arthritis, osteoarthritis, psoriatic arthritis, goutyarthritis, reactive arthritis, rheumatoid arthritis or Reiter'sarthritis), lumbosacral pain, musculo-skeletal pain, headache, migraine,muscle ache, lower back pain, neck pain, toothache, dental/maxillofacialpain, visceral pain and the like. One or more of the painful conditionscontemplated herein can comprise mixtures of various types of painprovided above and herein (e.g. nociceptive pain, inflammatory pain,neuropathic pain, etc.). In some embodiments, a particular pain candominate. In other embodiments, the painful condition comprises two ormore types of pains without one dominating. A skilled clinician candetermine the dosage to achieve a therapeutically effective amount for aparticular subject based on the painful condition.

In certain embodiments, the disease is a psychiatric disorder. The term“psychiatric disorder” refers to a disease of the mind and includesdiseases and disorders listed in the Diagnostic and Statistical Manualof Mental Disorders—Fourth Edition (DSM-IV), published by the AmericanPsychiatric Association, Washington D. C. (1994). Psychiatric disordersinclude anxiety disorders (e.g., acute stress disorder agoraphobia,generalized anxiety disorder, obsessive-compulsive disorder, panicdisorder, posttraumatic stress disorder, separation anxiety disorder,social phobia, and specific phobia), childhood disorders, (e.g.,attention-deficit/hyperactivity disorder, conduct disorder, andoppositional defiant disorder), eating disorders (e.g., anorexia nervosaand bulimia nervosa), mood disorders (e.g., depression, bipolardisorder, cyclothymic disorder, dysthymic disorder, and major depressivedisorder), personality disorders (e.g., antisocial personality disorder,avoidant personality disorder, borderline personality disorder,dependent personality disorder, histrionic personality disorder,narcissistic personality disorder, obsessive-compulsive personalitydisorder, paranoid personality disorder, schizoid personality disorder,and schizotypal personality disorder), psychotic disorders (e.g., briefpsychotic disorder, delusional disorder, schizoaffective disorder,schizophreniform disorder, schizophrenia, and shared psychoticdisorder), substance-related disorders (e.g., alcohol dependence,amphetamine dependence, cannabis dependence, cocaine dependence,hallucinogen dependence, inhalant dependence, nicotine dependence,opioid dependence, phencyclidine dependence, and sedative dependence),adjustment disorder, autism, delirium, dementia, multi-infarct dementia,learning and memory disorders (e.g., amnesia and age-related memoryloss), and Tourette's disorder.

In certain embodiments, the disease is a metabolic disorder. The term“metabolic disorder” refers to any disorder that involves an alterationin the normal metabolism of carbohydrates, lipids, proteins, nucleicacids, or a combination thereof. A metabolic disorder is associated witheither a deficiency or excess in a metabolic pathway resulting in animbalance in metabolism of nucleic acids, proteins, lipids, and/orcarbohydrates. Factors affecting metabolism include the endocrine(hormonal) control system (e.g., the insulin pathway, theenteroendocrine hormones including GLP-1, PYY or the like), the neuralcontrol system (e.g., GLP-1 in the brain), or the like. Examples ofmetabolic disorders include diabetes (e.g., Type I diabetes, Type IIdiabetes, gestational diabetes), hyperglycemia, hyperinsulinemia,insulin resistance, and obesity.

In certain embodiments, the disease is a cardiovascular disease. Incertain embodiments, the disease is a cardiovascular disease. In certainembodiments, the disease is atherogenesis or atherosclerosis. In certainembodiments, the disease is arterial stent occlusion, heart failure(e.g., congestive heart failure), a coronary arterial disease,myocarditis, pericarditis, a cardiac valvular disease, stenosis,restenosis, in-stent-stenosis, angina pectoris, myocardial infarction,acute coronary syndromes, coronary artery bypass grafting, acardio-pulmonary bypass procedure, endotoxemia, ischemia-reperfusioninjury, cerebrovascular ischemia (stroke), renal reperfusion injury,embolism (e.g., pulmonary, renal, hepatic, gastro-intestinal, orperipheral limb embolism), or myocardial ischemia.

In certain embodiments, the method further comprises administering tothe subject in need thereof an additional therapy. In certainembodiments, the additional therapy is an additional pharmaceuticalagent. In certain embodiments, the additional therapy is an additionalnutraceutical agent. The pharmaceutical and nutraceutical compositionsof the present disclosure and the additional therapy may show synergy inthe methods and uses of the present disclosure.

In another aspect, the invention is directed to a method for increasingenergy levels of a subject, for reducing fatigue or drowsiness in asubject, or for increasing alertness in a subject, the method comprisingadministering to the subject any composition described herein; or acompound of Formula (I):

or a pharmaceutically or nutraceutically acceptable salt, hydrate, orsolvate thereof;

wherein each Y is independently hydrogen or deuterium; and

at least one Y is deuterium.

In another aspect, the invention is directed to a method for treatingobesity in a subject, for causing weight loss in a subject, forincreasing metabolic rate in a subject, for reducing appetite in asubject, or for increasing energy expenditure in a subject, the methodcomprising administering to the subject a compound of Formula (I):

or a pharmaceutically or nutraceutically acceptable salt, hydrate, orsolvate thereof;

wherein each Y is independently hydrogen or deuterium; and

at least one Y is deuterium.

In another aspect, the invention is directed to a method for increasingurine output in a subject, for increasing sodium excretion in a subject,or for reducing edema in a subject, the method comprising administeringto the subject a compound of Formula (I):

or a pharmaceutically or nutraceutically acceptable salt, hydrate, orsolvate thereof;

wherein each Y is independently hydrogen or deuterium; and

at least one Y is deuterium.

In another aspect, the invention is directed to a method for treating apain disorder in a subject, the method comprising administering to thesubject a compound of Formula (I):

or a pharmaceutically or nutraceutically acceptable salt, hydrate, orsolvate thereof;

wherein each Y is independently hydrogen or deuterium; and

at least one Y is deuterium.

In another aspect, the pain disorder is migraine, arthritis, headache,back pain, bursitis, chronic pain, acute pain, musculoskeletal pain,osteoarthritis, psoriatic arthritis, rheumatoid arthritis, or sciatica.In another aspect, the pain disorder is migraine. In another aspect, thepain disorder is arthritis. In another aspect, the pain disorder isheadache. In another aspect, the pain disorder is back pain. In anotheraspect, the pain disorder is bursitis. In another aspect, the paindisorder is chronic pain. In another aspect, the pain disorder is acutepain. In another aspect, the pain disorder is musculoskeletal pain. Inanother aspect, the pain disorder is osteoarthritis. In another aspect,the pain disorder is psoriatic arthritis. In another aspect, the paindisorder is rheumatoid arthritis. In another aspect, the pain disorderis sciatica. In another aspect, the pain disorder is migraine orheadache.

In another aspect, the invention is directed to a method for treatingapnea in a subject, the method comprising administering to the subject acompound of Formula (I):

or a pharmaceutically or nutraceutically acceptable salt, hydrate, orsolvate thereof;

wherein each Y is independently hydrogen or deuterium; and

at least one Y is deuterium.

In another aspect, the apnea is sleep apnea. In another aspect, thesleep apnea is obstructive sleep apnea, central sleep apnea, apnea ofprematurity, or complex sleep apnea syndrome. In another aspect, theapnea is apnea of prematurity. In another aspect, the subject is aneonate, preterm infant, premature infant, or low birthweight infant. Inanother aspect, the subject is an adult.

In another aspect, the invention is directed to a method for treatinghypotension in a subject, the method comprising administering to thesubject a compound of Formula (I):

or a pharmaceutically or nutraceutically acceptable salt, hydrate, orsolvate thereof;

wherein each Y is independently hydrogen or deuterium; and

at least one Y is deuterium.

In another aspect, the hypotension is orthostatic hypotension,postprandial hypotension, or multiple system atrophy with orthostatichypotension. In another aspect, the hypotension is orthostatichypotension. In another aspect, the hypotension is multiple systematrophy with orthostatic hypotension.

In another aspect, the invention is directed to a method for treating anencephalopathy in a subject, the method comprising administering to thesubject a compound of Formula (I):

or a pharmaceutically or nutraceutically acceptable salt, hydrate, orsolvate thereof;

wherein each Y is independently hydrogen or deuterium; and

at least one Y is deuterium.

In another aspect, the encephalopathy is chronic traumaticencephalopathy, glycine encephalopathy, Hashimoto's encephalopathy,hepatic encephalopathy, hypertensive encephalopathy, hypoxic ischemicencephalopathy, toxic metabolic encephalopathy, infectiousencephalopathy, uremic encephalopathy, or Wernicke encephalopathy. Inanother aspect, the encephalopathy is chronic traumatic encephalopathy.In another aspect, the encephalopathy is glycine encephalopathy. Inanother aspect, the encephalopathy is Hashimoto's encephalopathy. Inanother aspect, the encephalopathy is hepatic encephalopathy. In anotheraspect, the encephalopathy is hypertensive encephalopathy. In anotheraspect, the encephalopathy is hypoxic ischemic encephalopathy. Inanother aspect, the encephalopathy is toxic metabolic encephalopathy. Inanother aspect, the encephalopathy is infectious encephalopathy. Inanother aspect, the encephalopathy is uremic encephalopathy. In anotheraspect, the encephalopathy is Wernicke encephalopathy.

In another aspect, the invention is directed to a method for treating aneurological or psychiatric disorder in a subject, the method comprisingadministering to the subject a compound of Formula (I):

or a pharmaceutically or nutraceutically acceptable salt, hydrate, orsolvate thereof;

wherein each Y is independently hydrogen or deuterium; and

at least one Y is deuterium.

In another aspect, the neurological or psychiatric disorder isnarcolepsy, Alzheimer's disease, attention deficit hyperactivitydisorder (ADHD), schizophrenia, Parkinson's disease, or depression. Inanother aspect, the neurological or psychiatric disorder is narcolepsy.In another aspect, the neurological or psychiatric disorder isAlzheimer's disease. In another aspect, the neurological or psychiatricdisorder is attention deficit hyperactivity disorder (ADHD. In anotheraspect, the neurological or psychiatric disorder is schizophrenia. Inanother aspect, the neurological or psychiatric disorder is Parkinson'sdisease. In another aspect, the neurological or psychiatric disorderdepression.

In another aspect, the invention is directed to a method for treating aninflammatory disorder in a subject, the method comprising administeringto the subject a compound of Formula (I):

or a pharmaceutically or nutraceutically acceptable salt, hydrate, orsolvate thereof;

wherein each Y is independently hydrogen or deuterium; and

at least one Y is deuterium.

In another aspect, the inflammatory disorder is a pulmonary inflammatorydisorder. In another aspect, the inflammatory disorder is asthma,chronic obstructive pulmonary disorder (COPD), pulmonary fibrosis, orinterstitial lung disease. In another aspect, the inflammatory disorderis asthma. In another aspect, the inflammatory disorder is chronicobstructive pulmonary disorder (COPD). In another aspect, theinflammatory disorder is pulmonary fibrosis. In another aspect, theinflammatory disorder is interstitial lung disease.

In any of the methods described herein, the maximum plasma concentration(C_(max)) of the compound of Formula (I) after administration of thecompound of Formula (I), or a pharmaceutically or nutraceuticallyacceptable salt, hydrate, or solvate, thereof, is substantially similarto that of non-isotopically enriched caffeine at an equivalent dose.

In another aspect, the maximum plasma concentration (C_(max)) of thecompound of Formula (I) after administration of the compound of Formula(I), or a pharmaceutically or nutraceutically acceptable salt, hydrate,or solvate thereof, is lower than that of non-isotopically enrichedcaffeine at an equivalent dose. In another aspect, the maximum plasmaconcentration (C_(max)) of the compound of Formula (I) afteradministration of the compound of Formula (I), or a pharmaceutically ornutraceutically acceptable salt, hydrate, or solvate thereof, is atleast 5%, 10%, 25%, or 50% lower than of non-isotopically enrichedcaffeine at an equivalent dose.

In any of the methods described herein, the time of maximum plasmaconcentration (T_(max)) of the compound of Formula (I) afteradministration of the compound of Formula (I), or a pharmaceutically ornutraceutically acceptable salt, hydrate, or solvate thereof, is longerthan that of non-isotopically enriched caffeine at an equivalent dose.

In another aspect, the time of maximum plasma concentration (T_(max)) ofthe compound of Formula (I) after administration of the compound ofFormula (I), or a pharmaceutically or nutraceutically acceptable salt,hydrate, or solvate thereof, is at least 5%, 10%, 25%, 50%, 100%, 200%,300%, or 400% longer than that of non-isotopically enriched caffeine atan equivalent dose.

In another aspect, the plasma half-life (t_(1/2)) of the compound ofFormula (I) after administration of the compound of Formula (I), or apharmaceutically or nutraceutically acceptable salt, hydrate, or solvatethereof, is longer than that of non-isotopically enriched caffeine at anequivalent dose.

In any of the methods described herein, the plasma half-life (t_(1/2))of the compound of Formula (I) after administration of the compound ofFormula (I), or a pharmaceutically or nutraceutically acceptable salt,hydrate, or solvate thereof, is at least 5%, 10%, 25%, 50%, 100%, 200%,300%, or 400% longer than that of non-isotopically enriched caffeine atan equivalent dose.

In any of the methods described herein, the maximum concentration(C_(max)) of the compound of Formula (I) in the central nervous system(CNS) of the subject after administration of the compound of Formula(I), or a pharmaceutically or nutraceutically acceptable salt, hydrate,or solvate thereof, is substantially similar to that of non-isotopicallyenriched caffeine at an equivalent dose.

In another aspect, the maximum concentration (C_(max)) of the compoundof Formula (I) in the central nervous system (CNS) of the subject afteradministration of the compound of Formula (I), or a pharmaceutically ornutraceutically acceptable salt, hydrate, or solvate thereof, is atleast 5%, 10%, 25%, or 50% lower than that of non-isotopically enrichedcaffeine at an equivalent dose.

In any of the methods described herein, the time of maximumconcentration (T_(max)) of the compound of Formula (I) in the centralnervous system (CNS) of the subject after administration of the compoundof Formula (I), or a pharmaceutically or nutraceutically acceptablesalt, hydrate, or solvate thereof, is longer than that ofnon-isotopically enriched caffeine at an equivalent dose.

In another aspect, the time of maximum concentration (T_(max)) of thecompound of Formula (I) in the central nervous system (CNS) of thesubject after administration of the compound of Formula (I), or apharmaceutically or nutraceutically acceptable salt, hydrate, or solvatethereof, is at least 5%, 10%, 25%, 50%, 100%, 200%, 300%, or 400% longerthan that of non-isotopically enriched caffeine at an equivalent dose.

In any of the methods described herein, the total systemic exposure(AUC) in plasma of the compound of Formula (I) after administration ofthe compound of Formula (I), or a pharmaceutically or nutraceuticallyacceptable salt, hydrate, or solvate thereof, is at least 5%, 10%, 25%,50%, 100%, or 200% greater than that of non-isotopically enrichedcaffeine at an equivalent dose.

In another aspect, the total systemic exposure (AUC) in plasma of thecompound of Formula (I) after administration of the compound of Formula(I), or a pharmaceutically or nutraceutically acceptable salt, hydrate,or solvate thereof, is greater than that of non-isotopically enrichedcaffeine at an equivalent dose.

In any of the methods described herein, the total systemic exposure(AUC) in the central nervous system of the compound of Formula (I) afteradministration of the compound of Formula (I), or a pharmaceutically ornutraceutically acceptable salt, hydrate, or solvate thereof, is atleast 5%, 10%, 25%, 50%, 100%, or 200% greater than that ofnon-isotopically enriched caffeine at an equivalent dose.

In another aspect, the total systemic exposure (AUC) in the centralnervous system of the compound of Formula (I) after administration ofthe compound of Formula (I), or a pharmaceutically or nutraceuticallyacceptable salt, hydrate, or solvate thereof, is greater than that ofnon-isotopically enriched caffeine at an equivalent dose.

In any of the methods described herein, the ratio of the total systemicexposure (AUC) in plasma of the compound of Formula (I) afteradministration of the compound of Formula (I), or a pharmaceutically ornutraceutically acceptable salt, hydrate, or solvate thereof, to thetotal systemic exposure (AUC) in the central nervous system of thecompound, is substantially similar to that of non-isotopically enrichedcaffeine at an equivalent dose.

In another aspect, the ratio of the total systemic exposure (AUC) inplasma of the compound of Formula (I) after administration of thecompound of Formula (I), or a pharmaceutically or nutraceuticallyacceptable salt, hydrate, or solvate thereof, to the total systemicexposure (AUC) in the central nervous system of the compound, is within20%, 15%, 10%, 5%, 2%, or 1% of that of non-isotopically enrichedcaffeine at an equivalent dose.

In another aspect, the side effects experienced after administration ofa compound of Formula (I), or a pharmaceutically or nutraceuticallyacceptable salt, hydrate, solvate, composition, or prodrug thereof, arereduced relative to the administration of non-isotopically enrichedcaffeine at an equivalent dose. In another aspect, the side effect isanxiety, insomnia, gastrointestinal issues (e.g., loose stools,diarrhea, stomach ulcers, gastroesophageal reflux, etc.),rhabdomyolysis, addiction, hypertension, rapid heart rate, atrialfibrillation, fatigue, irritability, nervousness, restlessness, nausea,or muscle tremors.

In any of the methods described herein, the side effects are reducedrelative to the administration of non-isotopically enriched caffeine atan equivalent dose. In another aspect, the side effect is anxiety,insomnia, gastrointestinal issues (e.g., loose stools, diarrhea, stomachulcers, gastroesophageal reflux, etc.), rhabdomyolysis, addiction,hypertension, rapid heart rate, atrial fibrillation, fatigue,irritability, nervousness, restlessness, nausea, or muscle tremors.

The representative examples, which follow, are intended to helpillustrate the invention, and are not intended to, nor should they beconstrued to, limit the scope of the invention. Indeed, variousmodifications of the invention and many further embodiments thereof, inaddition to those shown and described herein, will become apparent tothose skilled in the art from the full contents of this document,including the examples which follow and the references to the scientificand patent literature cited herein. It should further be appreciatedthat, unless otherwise indicated, the entire contents of each of thereferences cited herein are incorporated herein by reference to helpillustrate the state of the art. The following examples containimportant additional information, exemplification and guidance, whichcan be adapted to the practice of this invention in its variousembodiments and the equivalents thereof.

These and other aspects of the present invention will be furtherappreciated upon consideration of the following Examples, which areintended to illustrate certain particular embodiments of the inventionbut are not intended to limit its scope, as defined by the claims.

EXAMPLES

In order that the disclosure described herein may be more fullyunderstood, the following examples are set forth. The synthetic andbiological examples described in this application are offered toillustrate the compounds, compositions, food products, beverages, andmethods provided herein and are not to be construed in any way aslimiting their scope.

Abbreviations AUC_(inf) Area under the concentration-time curve fromtime zero extrapolated to infinity AUC_(last) Area under theconcentration-time curve from time zero to the last quantifiableconcentration BQL Below quantitation limit C_(max) Maximum concentrationobserved CV Coefficient of variation Hr Hour(s) LC-MS/MS LiquidChromatography Tandem Mass Spectrometry LLOQ Lower limit of quantitationMin Minute(s) n Number of samples NA Not applicable No. Number NR Notreported QC Quality control rpm Revolutions per minute SD Standarddeviation Sec Second(s) Std Standard T_(1/2) Terminal half-life T_(max)Time of observed maximum concentration ULOQ Upper limit of quantitationv VolumeCompounds

Compounds delineated herein include salt, hydrate and solvates thereof.They include all compounds delineated in schemes herein, whetherintermediate or final compounds in a process.

Compounds of the invention can be obtained from natural sources or madeor modified made by means known in the art of organic synthesis. Methodsfor optimizing reaction conditions, if necessary minimizing competingby-products, are known in the art. Reaction optimization and scale-upmay advantageously utilize high-speed parallel synthesis equipment andcomputer-controlled microreactors (e.g. Design And Optimization inOrganic Synthesis, 2^(nd) Edition, Carlson R, Ed, 2005; Elsevier ScienceLtd.; Jähnisch, K et al, Angew. Chem. Int. Ed. Engl. 2004 43: 406; andreferences therein). Additional reaction schemes and protocols may bedetermined by the skilled artesian by use of commercially availablestructure-searchable database software, for instance, SciFinder® (CASdivision of the American Chemical Society) and CrossFire Beilstein®(Elsevier MDL), or by appropriate keyword searching using an internetsearch engine such as Google® or keyword databases such as the US Patentand Trademark Office text database.

Caffeine and D9-caffeine (Compound 14) were purchased from theSigma-Aldrich and stored at room temperature upon receipt.

Pharmacokinetic (PK) Study Design

Two groups of fasted male Sprague-Dawley rats (12 animals per group)were administered an oral single dose of caffeine in deionized water(Group 1) or D9-caffeine in deionized water (Group 2) at a target doselevel of 2 mg/kg.

Serial blood samples were collected from three animals per group pertimepoint prior to dosing and at 0.25, 0.5, 1, 2, 3 4, 6, 8, 10, 12, and14-hours post dose. No more than three blood samples were collected fromindividual animals with the last sample being a terminal blood draw.Terminal brain samples were collected from three animals per group at 1,4, 8, and 14-hours post dose. Blood samples were collected into tubescontaining sodium heparin, and then processed for plasma and storedfrozen until bioanalysis. Brain samples were collected following theterminal blood collection, rinsed with saline, and stored frozen untilbioanalysis.

Plasma and brain samples were analyzed for caffeine and D9-caffeine(Compound 14) concentration using a liquid chromatography-tandem massspectrometry (LC-MS/MS) method. Non-compartmental pharmacokineticparameter estimates were calculated from the mean plasmaconcentration-time data.

The results demonstrate that D9-caffeine (Compound 14) provides a highersystemic exposure (as measured by AUC) and a longer half-life than acorresponding dose of caffeine in vivo.

Extraction Procedure, LC and MS Conditions, and Data Analysis

Table 1 captures the extraction procedures, liquid chromatography (LC)and mass spectrometry (MS) conditions, and the data analysis methodsemployed.

TABLE 1 Sample Aliquot 10 μL of sample (calibration standards, qualityExtraction control samples, blanks and study samples) into a 96-wellplate Add 60 μL of internal standard spiking solution (100 ng/mL¹³C₃-Caffeine in acetonitrile) to each well, except for double blanks towhich 60 μL of acetonitrile was added per well Vortex-mix Centrifugeat >3000 rpm for 5 minutes Transfer supernatant (50 μL) into a clean96-well plate containing 50 μL of water per well Vortex-mix LCConditions Column Waters Atlantis T3; 3 um, 30 × 2.1 mm Temperature 45°C. Mobile 0.1% formic acid in 95:5 (v:v) water: acetonitrile Phase AMobile 0.1% formic acid in 50:50 (v:v) acetonitrile: methanol Phase BGradient Time (sec) % Mobile Phase B Flow (mL/min) 15 5 0.500 60 950.500 5 95 0.500 30 95 0.500 40 5 0.500 MS Conditions MS/MS API-5500Ionization Electrospray, positive ion Method Resolution Unit/Unit Source550° C. Temperature Transitions (m/z) Caffeine: 195.1/138.1 D9-Caffeine: 204.1/144.1 ¹³C₃- Caffeine 198.1/140.1 (IS): Data AnalysisAcquisition Analyst ® (Applied Biosystems Sciex) and ProcessingRegression Linear, 1/x² Type Acceptance Criteria Calibration At least75% of the total number of calibration standards Standards are within±15.0% of their nominal concentrations (±20.0% at LLOQ). At least onecalibration standard at the LLOQ and at the ULOQ must be acceptable.Accuracy (bias) of the mean values are within ±15.0% from nominalconcentration (±20.0% at LLOQ), and precision (CV) is ≤15.0% (≤20.0% atLLOQ) Quality At least two-thirds of replicates are within ±15.0%Controls of their nominal concentrations (±20.0% at LLOQ). Accuracy(bias) of the mean values are within ±15.0% from nominal concentration(±20.0% at LLOQ), and precision (CV) is ≤15.0% (≤20.0% at LLOQ)Preparation of Dose Formulations

Dose formulations were prepared on the day of dosing.

For Group 1, the dosing formulation was prepared at a targetconcentration of 0.2 mg/mL by adding caffeine (10.00 mg) to deionizedwater (49.778 g), vortex-mixing and sonicating.

For Group 2, the dosing formulation was prepared at a targetconcentration of 0.2 mg/mL by adding D9-caffeine (10.04 mg) to deionizedwater (49.792 g), vortex-mixing and sonicating.

After dosing, the formulations were stored in a −80° C. freezer.

Rat Acclimation and Housing

Male Sprague-Dawley rats were received from Envigo RMS on 18 Mar. 2019.After an acclimation period of three days, 24 males were assigned to thestudy based on acceptable health. Animals assigned to the study wereuniquely identified by tail marking (indelible ink) and cage cards.

Animals were housed in Innovive® disposable micro-isolator cages (1 to 3animals per cage). Teklad Global Diets™ (Envigo) 18% Protein Rodent Diet2018 and tap water were provided ad libitum until the evening prior todosing. Animals were fasted overnight prior to dose administration.

Animal quarters were maintained at a temperature between 20° C. to 26°C. (68° F. to 79° F.), a relative humidity of 30% to 70%, and with anair flow of at least 10 changes per hour. The light/dark cycle was setfor 12-hour intervals, but the cycle was interrupted for the performanceof study procedures.

After collection of the final blood samples, the study animals wereeuthanized by carbon dioxide asphyxiation in accordance with theAmerican Veterinary Medical Association Guidelines on Euthanasia(current version).

Dose Administration

Animals were fasted overnight prior to dose administration. Water wasprovided ad libitum. Food was returned after the collection of the4-hour samples. Two groups of male Sprague-Dawley rats (12 animals pergroup) were administered a single dose of caffeine in deionized water(Group 1) or D9-caffeine (Compound 14) in deionized water (Group 2) at atarget dose level of 2 mg/kg.

Prior to dosing, the body weight of each animal was recorded. Doses(rounded to the nearest 0.001 mL) were calculated based on thepretreatment body weight (kg) and a dose volume of 10 mL/kg. Oral doseswere administered using a ball tipped feeding needle. Dosing syringeswere weighed immediately prior to and immediately after dosing eachanimal, and the quantity of formulation administered to each animal wasdetermined from the difference in syringe weights.

Sample Collection and Processing

Serial blood samples (˜300 μL) were collected from three animals pergroup per timepoint into tubes containing sodium heparin prior to dosingand at 0.25, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, and 14-hours post dose.Blood was collected from each animal on three occasions with the lastblood draw coinciding with the sacrifice of the animal. Blood sampleswere stored on wet ice until being processed for plasma viacentrifugation (3500 g for 10 minutes at 5° C.) within 30 minutes ofcollection. Plasma samples were transferred into matrix tubes and storedin a freezer set to maintain a temperature of −80° C. until analysis.

Immediately after the 1, 4, 8 and 14-hour blood collections, threeanimals/group were euthanized and the brain was dissected out of eachrat. The brains were rinsed with saline and dried, placed in pre-weighedconical tubes, and flash frozen in liquid nitrogen. Brain weights werecalculated for each sample. Brains were stored in a freezer set tomaintain a temperature of −80° C.

Bioanalysis

Rat plasma and brain samples were analyzed for concentrations ofcaffeine and D9-caffeine (Compound 14) using a qualified LC-MS/MSmethod. The extraction procedure and analytical method are detailed inTable 1.

Pharmacokinetic Analysis

Pharmacokinetic parameter estimates were calculated from the caffeineand D9-caffeine (Compound 14) plasma concentration-time data generatedfrom combined animal plasma data using nominal sampling times andnon-compartmental methods. The concentration-time data were analyzed tofit an extra-vascular (oral gavage) dosing plasma analysis model (200)using the software WinNonlin Phoenix version 6.3 (Pharsight). Thepharmacokinetic parameters assessed include, as appropriate: T_(1/2)(terminal half-life); T_(max) (time of peak concentration); C_(max)(peak or maximum concentration); AUC_(last) (computed from time zero tothe time of the last positive Y value), and AUC_(INF) (area under aconcentration of analyte vs. time calculated using zero to infinity).

Areas-under-the-plasma concentration-time curves (AUC) were estimatedusing the linear trapezoidal rule. The area through the time (T_(last))of the last observable concentration (C_(last)) is reported asAUC_(last). AUC extrapolated to infinity, (AUC_(INF)) was estimated byadding AUC_(last) and the ratio of C_(last)/λ_(z), where λ_(z) is theterminal rate constant. Apparent T_(1/2) was calculated using the slopeof the log-linear terminal phase of the concentration-time curve,defined by a minimum of three plasma concentration-time points.Half-lives are reported if the correlation for the regression line, asmeasured by r squared, is ≥0.9, when rounded.

Results

Dose Administration

Two groups of male Sprague-Dawley rats (12 animals per group) wereadministered a single dose of caffeine in deionized water (Group 1) orD9-caffeine in deionized water (Group 2) at a target dose level of 2mg/kg.

In rats treated with caffeine (Group 1), the dose administered,determined gravimetrically and based on nominal concentration, rangedfrom 1.970 to 2.023 mg/kg (−1.48% to 1.21% dosing variance). In ratstreated with D9-caffeine (Group 2), the dose administered, determinedgravimetrically and based on nominal concentration, ranged from 1.971 to2.017 mg/kg (−1.43% to 0.85% dosing variance). Dose administration dataare reported in Table 2.

TABLE 2 Protocol- Animal Formulation Nominal Specified Dosing Group TestAnimal Weight Administered Concentration^(a) Dose Administered DoseVariance Number Article Number (kg) (g) (mg/mL) (mg) (mg/kg) (mg/kg) (%)1 Caffeine 1 0.339 3.388 0.2 0.678 1.999 2 −0.06 2 0.333 3.331 0.2 0.6662.001 2 0.03 3 0.338 3.338 0.2 0.668 1.975 2 −1.24 4 0.380 3.771 0.20.754 1.985 2 −0.76 5 0.341 3.450 0.2 0.690 2.023 2 1.17 6 0.328 3.3050.2 0.661 2.015 2 0.76 7 0.351 3.527 0.2 0.705 2.010 2 0.48 8 0.3483.522 0.2 0.704 2.024 2 1.21 9 0.331 3.334 0.2 0.667 2.015 2 0.73 100.332 3.324 0.2 0.665 2.002 2 0.12 11 0.332 3.346 0.2 0.669 2.016 2 0.7812 0.317 3.123 0.2 0.625 1.970 2 −1.48 2 D9- 13 0.345 3.476 0.2 0.6952.015 2 0.75 Caffeine 14 0.346 3.479 0.2 0.696 2.011 2 0.55 15 0.3413.439 0.2 0.688 2.017 2 0.85 16 0.343 3.455 0.2 0.691 2.015 2 0.73 170.345 3.473 0.2 0.695 2.013 2 0.67 18 0.360 3.592 0.2 0.718 1.996 2−0.22 19 0.378 3.726 0.2 0.745 1.971 2 −1.43 20 0.330 3.304 0.2 0.6612.002 2 0.12 21 0.361 3.628 0.2 0.726 2.010 2 0.50 22 0.326 3.258 0.20.652 1.999 2 −0.06 23 0.351 3.500 0.2 0.700 1.994 2 −0.28 24 0.3703.680 0.2 0.736 1.989 2 −0.54 ^(a)Assumes a density of 1.0 g/mL.Sample Collection and Processing

Samples were obtained within 5% of the scheduled time with the followingexceptions: the 0.5-hour blood sample from Animal No. 1 (11.61%) and the1-hour brain samples from Animal No. 1 (8.19%), No. 2 (7.47%), No. 3(7.06%), No. 4 (7.39%), No. 5 (8.00%), and No. 6 (6.72%).

Concentrations in Plasma

Mean caffeine concentrations in plasma following an oral (gavage) doseof caffeine to male Sprague-Dawley rats are summarized in Table 3 anddata for individual animals are reported in Table 4. Mean D9-caffeine(Compound 14) concentrations in plasma following an oral (gavage) doseof D9-caffeine (Compound 14) to male Sprague-Dawley rats are summarizedin Table 5. Data for individual animals are reported in Table 6. Meancaffeine and D9-caffeine plasma concentration-time profiles are plottedin FIG. 1.

Following administration of 2 mg/kg of caffeine or D9-caffeine (Compound14), measurable plasma concentrations of caffeine or D9-caffeine(Compound 14) were detected in all animals evaluated at each time pointthrough 14 hours post dose.

TABLE 3 Group 1: Mean (n = 3/time point) Caffeine Concentrations inPlasma Following an Oral (Gavage) Dose of Caffeine to Fasted MaleSprague-Dawley Rats at a Target Dose Level of 2 mg/kg Time Concentration(ng/mL) (hour) Mean SD % CV Pre BQL NA NA 0.25 2423 219 9.1 0.5 240792.4 3.8 1 2643 123 4.7 2 2067 32.1 1.6 3 2030 65.6 3.2 4 1820 121 6.7 61199 341 28.4 8 849 340 40.1 10 344 118 34.3 12 171 74.4 43.5 14 97.151.9 53.4

TABLE 4 Group 1: Caffeine Concentrations in Plasma Following an Oral(Gavage) Dose of Caffeine to Fasted Male Sprague Dawley Rats at a TargetDose Level of 2 mg/kg Time Concentration (ng/mL) Point Animal No. (hr) 12 3 4 5 6 7 8 9 10 11 12 Pre BQL BQL BQL BQL BQL BQL BQL BQL BQL BQL BQLBQL 0.25 2250 2670 2350 — — — — — — — — — 0.5 2460 2300 2460 — — — — — —— — — 1 2540 2610 2780 — — — — — — — — — 2 — — — 2080 2030 2090 — — — —— — 3 — — — 2100 1970 2020 — — — — — — 4 — — — 1710 1800 1950 — — — — —— 6 — — — 1470 1310 816 — — — 8 — — — — — — 1150 916 480 — — — 10 — — —— — — — — — 439 382 212 12 — — — — — — — — — 231 194 87.7 14 — — — — — —— — — 136 117 38.2 — Not a scheduled time point. BQL: Below quantitationlimit (<3.00 ng/mL)

TABLE 5 Group 2: Mean (n = 3/time point) D9-Caffeine Concentrations inPlasma Following an Oral (Gavage) Dose of D9-Caffeine to Fasted MaleSprague-Dawley Rats at a Target Dose Level of 2 mg/kg Time Concentration(ng/mL) (hour) Mean SD % CV Pre BQL NA NA 0.25 1717 230 13.4 0.5 1743261 15.0 1 2093 145 6.9 2 2340 72.1 3.1 3 2357 73.7 3.1 4 2267 76.4 3.46 1793 55.1 3.1 8 1550 108 7.0 10 1210 78.1 6.5 12 897 70.0 7.8 14 68276.4 11.2

TABLE 6 Group 2: D9-Caffeine Concentrations in Plasma Following an Oral(Gavage) Dose of D9-Caffeine to Fasted Male Sprague Dawley Rats at aTarget Dose Level of 2 mg/kg Time Concentration (ng/mL) Point Animal No.(hour) 13 14 15 16 17 18 19 20 21 22 23 24 Pre BQL BQL BQL BQL BQL BQLBQL BQL BQL BQL BQL BQL 0.25 1730 1480 1940 — — — — — — — — — 0.5 16801520 2030 — — — — — — — — — 1 2020 2000 2260 — — — — — — — — — 2 — — —2400 2360 2260 — — — — — — 3 — — — 2330 2440 2300 — — — — — — 4 — — —2350 2250 2200 — — — — — — 6 — — — — — — 1850 1740 1790 — — — 8 — — — —— — 1670 1460 1520 — — — 10 — — — — — — — — — 1160 1170 1300 12 — — — —— — — — — 910 821 959 14 — — — — — — — — — 633 643 770 — Not a scheduledtime point. BQL: Below quantitation limit (<3.00 ng/mL)Concentrations in Brain

Mean caffeine concentrations in brain following an oral (gavage) dose ofcaffeine to male Sprague-Dawley rats are summarized in Table 7. Data forindividual animals are reported in Table 8. Mean D9-caffeine (Compound14) concentrations in brain following an oral (gavage) dose ofD9-caffeine (Compound 14) to male Sprague-Dawley rats are summarized inTable 9. Data for individual animals are reported in Table 10. Meancaffeine and D9-caffeine (Compound 14) brain concentration-time profilesare shown in FIG. 2.

Following administration of 2 mg/kg of caffeine or D9-caffeine (Compound14), measurable brain concentrations of caffeine or D9-caffeine(Compound 14) were detected in all animals evaluated at each time pointthrough 14 hours post dose.

TABLE 7 Group 1: Mean (n = 3/time point) Caffeine Concentrations inBrain Following an Oral (Gavage) Dose of Caffeine to Fasted MaleSprague-Dawley Rats at a Target Dose Level of 2 mg/kg Time Concentration(ng/g) (hour) Mean SD % CV 1 1910 118 6.2 4 1210 75 6.2 8 553 245 44.314 62.6 33.7 53.8

TABLE 8 Group 1: Caffeine Concentrations in Brain Following an Oral(Gavage) Dose of Caffeine to Fasted Male Sprague Dawley Rats at a TargetDose Level of 2 mg/kg Time Concentration (ng/g) Point Animal No. (hour)1 2 3 4 5 6 7 8 9 10 11 12 1 2010 1940 1780 — — — — — — — — — 4 — — —1140 1200 1290 — — — — — — 8 — — — — — — 715 672 271 — — — 14 — — — — —— — — — 84 80 23.8 — Not a scheduled time point.

TABLE 9 Group 2: Mean (n = 3/time point) D9-Caffeine Concentrations inBrain Following an Oral (Gavage) Dose of D9-Caffeine to Fasted MaleSprague-Dawley Rats at a Target Dose Level of 2 mg/kg Time Concentration(ng/g) (hour) Mean SD % CV 1 1537 153 9.9 4 1643 80.8 4.9 8 1153 112 9.714 463 47.5 10.3

TABLE 10 Group 2: D9-Caffeine Concentrations in Brain Following an Oral(Gavage) Dose of D9-Caffeine to Fasted Male Sprague Dawley Rats at aTarget Dose Level of 2 mg/kg Time Concentration (ng/g) Point Animal No.(hour) 13 14 15 16 17 18 19 20 21 22 23 24 1 1570 1370 1670 — — — — — —— — — 4 — — — 1570 1730 1630 — — — — — — 8 — — — — — — 1280 1070 1110 —— — 14 — — — — — — — — — 465 414 509 — Not a scheduled time point.Pharmacokinetics

Mean pharmacokinetic parameter estimates for caffeine and D9-caffeine(Compound 14) following an oral dose of caffeine or D9-caffeine(Compound 14) to male Sprague-Dawley rats are reported in Table 11 forplasma and Table 12 for brain.

Following oral dose administration of caffeine at 2 mg/kg, the T_(1/2),C_(max) and AUC_(last) in plasma were 1.9 hr, 2600 ng/mL and 16000hr*ng/mL, respectively. Following oral dose administration ofD9-caffeine (Compound 14) at 2 mg/kg, the T_(1/2), C_(max) andAUC_(last) in plasma were 5 hr, 2400 ng/mL and 22000 hr*ng/mL,respectively. D9-caffeine (Compound 14) provided a higher AUC exposureand a longer half-life than a corresponding dose of caffeine in plasma.

Due to differences in the molecular weights of caffeine (MW=195.1) andD9-caffeine (MW=204.1), fewer molecules of D9-caffeine were administeredat a 2 mg/kg dose level than caffeine. Molecular weight correctedC_(max), AUC_(last), and AUC_(inf) values in plasma are presented inTable 13 to enable comparison between caffeine and D9-caffeine (Compound14). While plasma C_(max) values were similar between D9-caffeine(Compound 14) and caffeine (C_(max,corr) ratio of 0.97), total systemicexposure (AUC_(inf)) to D9-caffeine (Compound 14) was approximately 77%higher (AUC_(inf,corr) ratio of 1.77).

Following oral dose administration of caffeine at 2 mg/kg, the C_(max)and AUC_(last) in brain were 1900 ng/mL and 11000 hr*ng/mL,respectively. Following oral dose administration of D9-caffeine(Compound 14) at 2 mg/kg, the C_(max) and AUC_(last) in brain were 1600ng/mL and 16000 hr*ng/mL, respectively. As in plasma, D9-caffeine(Compound 14) provided a higher AUC exposure than a corresponding doseof caffeine in brain. The brain/plasma AUC_(last) ratios were similarand were 0.69 and 0.73 for caffeine and D9-caffeine (Compound 14),respectively.

Molecular weight corrected C_(max) and AUC_(last) values in brain arepresented in Table 14. Brain C_(max) values were slightly lower forD9-caffeine (Compound 14) than caffeine (C_(max,corr) ratio of 0.88)although these differences may have been related to the low number oftime points evaluated and differences in T_(max). However, total brainexposure (AUC_(last,corr)) to D9-caffeine (Compound 14) wasapproximately 52% higher than caffeine (AUC_(last,corr) ratio of 1.52).

TABLE 11 Plasma Pharmacokinetic Parameters for Caffeine and D9-CaffeineFollowing Oral (Gavage) Administration of Caffeine or D9-Caffeine toFasted Male Sprague Dawley Rats at a Target Dose Level of 2 mg/kgPharmacokinetic Parameter Group T_(1/2) T_(max) C_(max) AUC_(last)AUC_(inf) No. Test Article (hour) (hour) (ng/mL) (hr · ng/mL) (hr *ng/mL) 1 Caffeine 1.9 1 2600 16000 16000 2 D9-Caffeine 5 3 2400 2200027000 T_(1/2) Terminal half life T_(max) The time of peak concentrationC_(max) The peak or maximum concentration AUC_(last) Computed from timezero to the time of the last positive Y value AUC_(inf) Area under aconcentration of analyte vs time calculated using zero to infinity

TABLE 12 Brain Pharmacokinetic Parameters for Caffeine and D9-CaffeineFollowing Oral (Gavage) Administration of Caffeine or D9-Caffeine toFasted Male Sprague Dawley Rats at a Target Dose Level of 2 mg/kgPharmacokinetic Parameter Ratio Ratio Group T_(max) C_(max) AUC_(last)AUC_(inf) Brain/Plasma Brain/Plasma No. Test Article (hour) (ng/mL) (hr· ng/mL) (hr * ng/mL) Cmax AUC_(last) 1 Caffeine 1 1900 11000 11000 0.730.69 2 D9-Caffeine 4 1600 16000 NR 0.67 0.73 NR Not reported due toinsufficient characterization of the terminal phase of theplasma-concentration profile T_(max) The time of peak concentrationC_(max) The peak or maximum concentration AUC_(last) Computed from timezero to the time of the last positive Y value AUC_(inf) Area under aconcentration of analyte vs time calculated using zero to infinity

TABLE 13 Molecular Weight Corrected Plasma Pharmacokinetic Parametersfor Caffeine and D9-Caffeine Following Oral (Gavage) Administration ofCaffeine or D9-Caffeine to Fasted Male Sprague Dawley Rats at a TargetDose Level of 2 mg/kg Pharmacokinetic Parameter Group C_(max,corr)C_(max) AUC_(last,corr) AUC_(last) AUC_(inf,corr) AUC_(inf) No. TestArticle (ng/mL) Ratio (hr · ng/mL) Ratio (hr * ng/mL) Ratio 1 Caffeine2486 15296 15296 2 D9-Caffeine 2400 0.97 22000 1.44 27000 1.77C_(max,corr) The peak or maximum concentration corrected for themolecular weight differences between the molecules (caffeine valuesmultiplied by 0.956) Ratio Ratio of D9-caffeine/molecular weightcorrected caffeine value AUC_(last,corr) Computed from time zero to thetime of the last positive Y value corrected for the molecular weightdifferences between the molecules (caffeine values multiplied by 0.956)AUC_(inf,corr) Area under a concentration of analyte vs time calculatedusing zero to infinity corrected for the molecular weight differencesbetween the molecules (caffeine values multiplied by 0.956)

TABLE 14 Molecular Weight Corrected Brain Pharmacokinetic Parameters forCaffeine and D9-Caffeine Following Oral (Gavage) Administration ofCaffeine or D9-Caffeine to Fasted Male Sprague Dawley Rats at a TargetDose Level of 2 mg/kg Pharmacokinetic Parameter C_(max,corr) C_(max)AUC_(last,corr) AUC_(last) Group No. Test Article (ng/mL) Ratio (hr ·ng/mL) Ratio 1 Caffeine 1816 10516 2 D9- 1600 0.88 16000 1.52 CaffeineC_(max,corr) The peak or maximum concentration corrected for themolecular weight differences between the molecules (caffeine valuesmultiplied by 0.956) Ratio Ratio of D9-caffeine/molecular weightcorrected caffeine value AUC_(last,corr) Computed from time zero to thetime of the last positive Y value corrected for the molecular weightdifferences between the molecules (caffeine values multiplied by 0.956)

EQUIVALENTS AND SCOPE

In the claims articles such as “a,” “an,” and “the” may mean one or morethan one unless indicated to the contrary or otherwise evident from thecontext. Claims or descriptions that include “or” between one or moremembers of a group are considered satisfied if one, more than one, orall of the group members are present in, employed in, or otherwiserelevant to a given product or process unless indicated to the contraryor otherwise evident from the context. The invention includesembodiments in which exactly one member of the group is present in,employed in, or otherwise relevant to a given product or process. Theinvention includes embodiments in which more than one, or all of thegroup members are present in, employed in, or otherwise relevant to agiven product or process.

Furthermore, the invention encompasses all variations, combinations, andpermutations in which one or more limitations, elements, clauses, anddescriptive terms from one or more of the listed claims is introducedinto another claim. For example, any claim that is dependent on anotherclaim can be modified to include one or more limitations found in anyother claim that is dependent on the same base claim. Where elements arepresented as lists, e.g., in Markush group format, each subgroup of theelements is also disclosed, and any element(s) can be removed from thegroup. It should it be understood that, in general, where the invention,or aspects of the invention, is/are referred to as comprising particularelements and/or features, certain embodiments of the invention oraspects of the invention consist, or consist essentially of, suchelements and/or features. For purposes of simplicity, those embodimentshave not been specifically set forth in haec verba herein. It is alsonoted that the terms “comprising,” “including,” and “containing” areintended to be open and permits the inclusion of additional elements orsteps. Where ranges are given, endpoints are included. Furthermore,unless otherwise indicated or otherwise evident from the context andunderstanding of one of ordinary skill in the art, values that areexpressed as ranges can assume any specific value or sub-range withinthe stated ranges in different embodiments of the invention, to thetenth of the unit of the lower limit of the range, unless the contextclearly dictates otherwise.

This application refers to various issued patents, published patentapplications, journal articles, and other publications, all of which areincorporated herein by reference. If there is a conflict between any ofthe incorporated references and the instant specification, thespecification shall control. In addition, any particular embodiment ofthe present invention that falls within the prior art may be explicitlyexcluded from any one or more of the claims. Because such embodimentsare deemed to be known to one of ordinary skill in the art, they may beexcluded even if the exclusion is not set forth explicitly herein. Anyparticular embodiment of the invention can be excluded from any claim,for any reason, whether or not related to the existence of prior art.

Those skilled in the art will recognize or be able to ascertain using nomore than routine experimentation many equivalents to the specificembodiments described herein. The scope of the present embodimentsdescribed herein is not intended to be limited to the above Description,but rather is as set forth in the appended claims. Those of ordinaryskill in the art will appreciate that various changes and modificationsto this description may be made without departing from the spirit orscope of the present invention, as defined in the following claims.

What is claimed is:
 1. A beverage comprising water and a compound ofFormula (I):

or a pharmaceutically or nutraceutically acceptable salt thereof;wherein each Y is independently hydrogen or deuterium; at least three Yatoms are deuterium; and the beverage comprises about 1 mg to about10,000 mg of the compound of Formula (I).
 2. The beverage of claim 1,wherein the beverage further comprises one or more of a flavoring and asweetener.
 3. The beverage of claim 1, wherein the beverage furthercomprises one or more of vitamins, minerals, co-factors, proteins,lipids, peptides, and amino acids.
 4. The beverage of claim 1, whereinthe beverage is an energy beverage.
 5. The beverage of claim 3, whereinthe beverage is a vitamin water.
 6. The beverage of claim 4, wherein theenergy beverage further comprises one or more of water, taurine,citicoline, vitamin B6, vitamin B12, folic acid, niacinamide,glucuronolactone, N-acetyl-L-tyrosine, L-phenylalanine, and malic acid.7. The beverage of claim 5, wherein the vitamin water further comprisesone or more of water, vitamin C, vitamin B5, vitamin B6, vitamin B12,magnesium, and pantothenic acid.
 8. The beverage of claim 1, wherein thebeverage comprises about 1 mg to about 400 mg of the compound of Formula(I), or a pharmaceutically or nutraceutically acceptable salt thereof.9. The beverage of claim 1, wherein the beverage comprises about 1 mg toabout 125 mg of the compound of Formula (I), or a pharmaceutically ornutraceutically acceptable salt thereof.
 10. The beverage of claim 1,wherein the beverage comprises about 5 mg to about 75 mg of the compoundof Formula (I), or a pharmaceutically or nutraceutically acceptable saltthereof.
 11. The beverage of claim 1, wherein the compound is selectedfrom the group consisting of:

or a pharmaceutically or nutraceutically acceptable salt thereof. 12.The beverage of claim 1, wherein the compound is

or a pharmaceutically or nutraceutically acceptable salt thereof. 13.The beverage of claim 1, such that the maximum plasma concentration(C_(max)) of the compound of Formula (I) after consumption of thebeverage is substantially similar to or lower than that ofnon-isotopically enriched caffeine at an equivalent dose.
 14. Thebeverage of claim 1, such that the maximum plasma concentration(C_(max)) of the compound of Formula (I) after consumption of thebeverage is at least 25% lower than that of non-isotopically enrichedcaffeine at an equivalent dose.
 15. The beverage of claim 1, such thatthe maximum plasma concentration (C_(max)) of the compound of Formula(I) after consumption of the beverage is at least 50% lower than that ofnon-isotopically enriched caffeine at an equivalent dose.
 16. Thebeverage of claim 1, such that the time of maximum plasma concentration(T_(max)) of the compound of Formula (I) after consumption of thebeverage is at least 10% longer than that of non-isotopically enrichedcaffeine at an equivalent dose.
 17. The beverage of claim 1, such thatthe time of maximum plasma concentration (T_(max)) of the compound ofFormula (I) after consumption of the beverage is at least 25% longerthan that of non-isotopically enriched caffeine at an equivalent dose.18. The beverage of claim 1, such that the time of maximum plasmaconcentration (T_(max)) of the compound of Formula (I) after consumptionof the beverage is at least 50% longer than that of non-isotopicallyenriched caffeine at an equivalent dose.
 19. The beverage of claim 1,such that the side effects are reduced relative to the consumption ofnon-isotopically enriched caffeine at an equivalent dose; wherein theside effect is anxiety, insomnia, gastrointestinal issues,rhabdomyolysis, addiction, hypertension, rapid heart rate, atrialfibrillation, fatigue, irritability, nervousness, restlessness, nausea,or muscle tremors.
 20. The beverage of claim 1, such that the maximumconcentration (C_(max)) of the compound of Formula (I) in the centralnervous system after consumption of the beverage is substantiallysimilar to that of non-isotopically enriched caffeine at an equivalentdose.
 21. The beverage of claim 1, such that the maximum concentration(C_(max)) of the compound of Formula (I) in the central nervous systemafter consumption of the beverage is at least 10% lower than that ofnon-isotopically enriched caffeine at an equivalent dose.
 22. Thebeverage of claim 1, such that the maximum concentration (T_(max)) ofthe compound of Formula (I) in the central nervous system afterconsumption of the beverage is at least 10% longer than that ofnon-isotopically enriched caffeine at an equivalent dose.
 23. Thebeverage of claim 1, such that the maximum concentration (T_(max)) ofthe compound of Formula (I) in the central nervous system afterconsumption of the beverage is at least 25% longer than that ofnon-isotopically enriched caffeine at an equivalent dose.